• Users Online: 163
  • Home
  • Print this page
  • Email this page
Home About us Editorial board Ahead of print Current issue Search Archives Submit article Instructions Subscribe Contacts Login 

 Table of Contents  
Year : 2014  |  Volume : 7  |  Issue : 2  |  Page : 93-103

Heat shock proteins and parasitic diseases: Part 1: Helminths

Department of Parasitology, Faculty of Medicine, Suez Canal University, Ismailia, Egypt

Date of Submission04-Sep-2014
Date of Acceptance25-Oct-2014
Date of Web Publication19-Jan-2015

Correspondence Address:
Sherif M Abaza
Department of Parasitology, Faculty of Medicine, Suez Canal University, Ismailia
Login to access the Email id

Source of Support: None, Conflict of Interest: None

DOI: 10.4103/1687-7942.149556

Rights and Permissions

Heat shock proteins (HSPs) are highly conserved and immunogenic proteins that are shared among diverse groups of mammals and microbial agents. They are categorized into different families according to their molecular weight. HSPs are involved in a variety of cellular processes and essential to cell survival. They are also implicated in immune pathology and clinical manifestations of a variety of autoimmune diseases and/or metabolic disorders such as atherosclerosis, diabetes and systemic lupus erythematosus. Their role in antigen cross-presentation and cancer immunotherapy as well as initiators of immune response and targets of autoimmune attack was also reported.
The objectives of the current presentation are to summarize the functional properties of HSPs and their role in innate and acquired immune responses, to throw light on their role in pathogenesis and parasites survival, to review the literature searching for new drug discovery and vaccine candidates for parasitic diseases, and finally to present their use in diagnosis and genotyping of some parasitic diseases.
Heat shock proteins (HSPs) are highly conserved and immunogenic proteins that are shared
1. Functional Properties of HSPs
1.1. Innate immunity
1.2. Adaptive immunity:
1.3. HSPs as cancer vaccines:
1.4. HSPs as infectious disease vaccines
1.5. HSPs and apoptosis
2. Heat Shock Proteins and Helminthes
2.1. Schistosoma spp.
2.2. Echinococcus spp.
2.3. Strongyloides spp.
2.4. Trichinella spiralis
2.5. Filarial nematodes
2.6. Other helminthes
Concluding Remarks
Abbreviations: APC: Antigen-presenting cell; CTL: Cytotoxic T-lymphocyte; E/S: Excretory/secretory; gp96: a member of HSP90 family; GST: Glutathione-S-transferase; HC: Hydatid cyst; HSP: Heat shock protein; IFN: Interferon; IL: Interleukin; MHC: major histocompatibility complex; NK: Natural killer; SEA: Soluble egg antigen; TLR: Toll-like receptor; TGF: Transforming growth factor; TNF: Tumor necrosis factor.

Keywords: adjuvants, autoimmunity, cytokines, heat-shock protein, immune pathology, parasitic diseases, stress proteins

How to cite this article:
Abaza SM. Heat shock proteins and parasitic diseases: Part 1: Helminths. Parasitol United J 2014;7:93-103

How to cite this URL:
Abaza SM. Heat shock proteins and parasitic diseases: Part 1: Helminths. Parasitol United J [serial online] 2014 [cited 2023 Nov 29];7:93-103. Available from: http://www.new.puj.eg.net/text.asp?2014/7/2/93/149556

  Introduction Top

Stress proteins or heat-shock proteins (HSPs) are among the highly conserved and immunogenic proteins shared among diverse groups of mammals and microbial agents [1] . HSPs were first recognized when the temperature of an incubator housing Drosophila was elevated, resulting in a change in the pattern of chromosomal puffing within the salivary glands [2] . In addition to heat, these proteins were found to be inducible upon exposure to a range of environmental stresses including oxygen deprivation, pH extremes, and nutrient deprivation [1] . HSP synthesis occurs at 5-15°C above the optimal organism temperature depending on its growth temperature range [3] . Generally, there is a transient increase in HSPs synthesis at a low level of temperature elevation, with a more sustained response observed at higher temperatures, a pattern of response observed in numerous organisms. For example, heat shock of BCG by increasing the temperature to 42°C results in the production of both HSP65 and HSP70, whereas HSP70 synthesis is more pronounced at 45°C. The investigators added that both heat-shock response and upregulation of HSPs are observed in all tissues and in both prokaryotic and eukaryotic organisms, indicating that it is a ubiquitous and critical biological response [4] .

These proteins have been categorized into different families according to their molecular weight, for example HSP110, HSP90, HSP70, HSP60, HSP40, HSP20-30, and HSP10 [5],[6] . For uniformity, Kampinga et al. [7] proposed guidelines for the nomenclature of various human HSP families. However, HSPs could be categorized into different functional systems, with some overlap. The HSP60-HSP10 system is involved in classical protein folding, whereas the HSP70-HSP40 system stabilizes peptides in a linear, unfolded state and delivers them to the HSP60-HSP10 system [8] . The HSP90 family is found predominantly in the cytoplasm and is believed to mediate the folding of specialized proteins such as steroid receptors and protein kinases [9] . Thermal tolerance, disaggregation, and unfolding of aggregated proteins for enzymatic digestion are handled by the larger HSP100 [10] . Being involved in such a variety of cellular processes, it is not surprising that the majority of HSPs (HSP60, HSP70, and HSP90) are fundamental to cell survival, and mutation or deletion of the major HSP which is often lethal to both cells and organisms. In addition, HSP70 plays important cellular roles in protein synthesis and modifying processes, and can combine with many kinds of antigenic peptides to form antigen peptide-HSP compounds [11] . Furthermore, several studies have shown the ability of HSP70 to target vaccine antigens to antigen-presenting cells (APCs), including dendritic cells and macrophages, increasing vaccine immunogenicity [12],[13],[14] . Some HSPs were implicated in immune pathology and clinical manifestations of a variety of autoimmune diseases and/or metabolic disorders such as atherosclerosis [15] , diabetes [16] , systemic lupus erythematosus [17] , and Behcet's disease [18] . The role of some HSPs in antigen cross-presentation [5] and cancer immunotherapy [19] has also been reported. In addition, these proteins are initiators of immune response as well as targets of autoimmune attack. That is Microbial HSPs may stimulate cellular or humoral immune responses that might be cross-reactive with the corresponding self-HSPs or other self-antigens, leading to the induction of autoimmunity [6] .

HSPs are also known to play critical roles in innate immunity as well as adaptive immunity. They are capable of: (a) Activating specific toll-like receptors (TLRs), (b) Inducing the maturation as well as influencing the activation of APCs, (c) Providing polypeptides for specific triggering of the acquired immune response, and (d) Playing a major role in cross-presentation of extracellular antigens (e.g. microbial antigens) in parenchymal cells by the class I pathway, resulting in the induction of CD8+cytotoxic T-lymphocyte responses [20],[21].

Besides, HSPs may facilitate the regulation of effector responses under appropriate conditions, which could be achieved by increasing the production of anti-inflammatory cytokines so as to deviate the cytokine balance from a proinflammatory type to an anti-inflammatory type [22] . HSPs may induce different types of regulatory T cells, including CD4 + Tr1 cells that secrete interleukin-10 (IL-10), and CD4 + CD25 + , and the transcription factor Forkhead-box-P3 (Foxp3)-expressing Treg that produce transforming growth factor-β (TGF-β) and IL-10 [5],[16],[19] .

It was shown that ATPase activity is essentially associated with the functions of the major HSP families. In addition to ADP/ATP, the peptide binding of the HSP90 system is under the control of calcium levels that induces the required conformational changes for peptide binding [9] . However, it was argued that HSPs constitute a third functional group of adjuvants [23] as they were recognized as major immunogens against pathogens [5] . It was shown that apart from acting as immunogenic antigens themselves, HSPs can also act as adjuvants to stimulate the immunogenicity of heterologous polypeptides to which they are either covalently or noncovalently coupled [24] .

The interactions between HSPs and parasitic diseases were reviewed in three articles. Shonhai et al. [25] focused on intracellular protozoan parasites such as Leishmania spp., Tryapnosoma cruzi, Plasmodium falciparum, and Toxoplasma gondii, and reviewed the role played by HSP90 in the development and growth of all of these intracellular parasites, as well as the biological functions of HSP70-HSP40 interactions. A year later, two review articles were published by Indian scientists focusing on HSP90. The potential importance of HSP90 in the growth and pathogenesis of several parasites such as Giardia, Plasmodium, Trypanosoma, and Leishmania was pointed out [26],[27] . Thus, according to their view, several HSP90 inhibitors are expected to be promising targets as new drugs and candidate vaccines.

The objectives of the current review are to: (a) Summarize the functional properties of HSPs and their role in innate and acquired immune responses, (b) Shed light on their role in the pathogenesis and survival of the majority of parasites, (c) Review the literature for new drug discovery (HSPs-specific inhibitors) and vaccine candidates for parasitic diseases, and (d) Present other considerable uses of these biomarkers in parasitic diseases.

Functional properties of heat-shock proteins

The highly conserved HSPs molecules are defined as molecular chaperones. Their main function is the correction of the folding or functional conformation of cell proteins (under stress). This correction improves the capability of the cell proteins to: (a) Achieve their native form, (b) Be directed to the functional location (e.g. endoplasmic reticulum or mitochondria), (c) Resist denaturing, and (d) Regain their natural status on the occurrence of partial denaturation.

In other words, HSPs play important roles in assembly of protein complexes and translocation of proteins across cellular compartments, as well as in several immunological processes [28] .

Innate immunity

In the old literature, it was believed that HSPs were 'danger-associated molecular patterns' because of being exclusively intracellular proteins only released on cellular injury or necrosis [29] . Now, it is apparent that HSPs are released from cells undergoing necrotic lysis in response to cytotoxic lymphocyte or natural killer action, or viral infections. Thus, especially members of HSP60, HSP70, and HSP90 families are capable of activating the innate immune response [30] . These members were shown to stimulate the human monocyte cell line (THP-1) to produce tumor necrosis factor (TNF-α), IL-6, and IL-8 [31] . This stimulation was mediated through different cellular receptors, either by TLR-4 (for HSP60), or CD14 (for HSP65), or by interacting with both TLR2 and 4, in a CD14-dependent manner (for HSP70) [21] . Another factor in the innate immunity role is the different abilities of HSP70s to stimulate cells of the innate immune system cells. It was found that this ability is dependent on the HSP source, whether mammalian or microbial, i.e. mycobacterial HSP70 stimulates the innate immune response, whereas some members of mammalian HSP70 may downregulate the immune response instead [32],[33] .

Adaptive immunity

Cancer studies on sarcomas indicated that HSPs could modulate the generation of adaptive immunity, and the investigators identified gp96 (a member of the HSP90 family) as the tumor rejection antigen. Immunization with gp96 elicited sarcoma-specific immunity, whereas gp96 purified from other chemically induced tumors did not elicit immunoprotection [34] . It was proposed that the immunogenicity was conferred by tumor-specific peptides associated with the HSP90 [35] , and this peptide binding is ATP/ADP dependent [36] . Interestingly, the uptake of HSP-chaperoned peptides by APCs is characterized by its availability for cross-presentation, which is the ability of exogenous antigens to enter the endogenous loading pathway of major histocompatibility complex (MHC) class I to produce CD8 + T cells [37] . The cross-presentation can occur either by the classical or the nonclassical MHC I loading, that is the vacuolar/endocytic or the cytosolic pathway [38] .

Heat-shock protein cancer vaccines

From preclinical to clinical trials (phase III), host gp96 purified from surgically removed tumors were utilized as cancer vaccines [39] . The clinical trials included tumors such as metastatic colorectal carcinoma, metastatic melanoma, non-Hodgkin lymphoma, pancreatic adenocarcinoma, and renal cell carcinoma [40] . The outcome of these clinical trials was variable, from statistically non-significant results in renal cell carcinoma, to a delay in disease progression compared with a group that received conventional chemotherapy and/or surgery in stage IV melanoma [41] . However, Colaco [42] reported that the majority of oncology animal studies used HSP70 instead of gp96.

Heat-shock proteins as infectious disease vaccines

Twenty years ago, a group of investigators found that recombinant mycobacterial HSP65 could activate murine macrophages in vivo, with intracellular inhibition of Listeria monocytogenes, but without protection against this pathogen [43] . Several studies were carried out to achieve protection in animal models using CD4 + and CD8 + T cells specific to HSP65 [44] and DNA plasmids encoding Mycobacterium leprae HSP65 [45] and HSP70 [46] . However, these studies yielded variable outcomes that were attributed to a general, rather than specific stimulation of inflammatory responses [47] . Recently, the native mycobacterial HSP16 administered with the adjuvant dioctadecyl ammonium bromide elicited protection in a TB mouse model and was capable of boosting an existing BCG vaccination [48] .

Heat-shock protein and apoptosis

In intracellular protozoons, apoptosis is considered a defense mechanism because apoptotic-infected cells are phagocytized by macrophages with parasite elimination. This phagocytosis is initiated by cellular signaling pathways, and the intracellular parasites prevent these pathways to ensure their survival in the infected cell [49] . In their study, the investigators showed that HSPs expression is directed against the parasite infection and could interfere with apoptosis by activation of the factors responsible for the regulation of anti-apoptotic molecules.

Heat-shock proteins and helminths

Schistosoma spp.

In the early 1990s, HSP70 was one of the antigens considered important candidates for the anti-schistosomiasis vaccine with paramyosin, triosephosphate isomerase (TPI), glutathione-S-transferase (GST), and the membrane protein Sm23 [50],[51] . Chinese investigators reported that water buffalo immunized with DNA vaccines of Schistosoma japonicum triosephosphate isomerase (SjCTPI) combined with the HSP70 plasmid and IL-12 resulted in protective immunity against schistosomiasis japonicum, with a variable reduction in all parameters (worm burden, fecal egg count, miracidial hatching rate, and hepatic egg counts) [52] . Two years later, two randomized double-blind control vaccine trials were conducted to determine the efficacy levels of the DNA vaccines encoding tetraspanin 23 kDa integral membrane protein (SjC23) or SjCTPI on their own, or when fused together with the dendritic cell targeting HSP70. They found that both vaccines incorporating HSP70 were more immunogenic and efficacious, as determined by the effect on egg burden [53] .

During 2010-2012, three Chinese articles were published on schistosomiasis vaccines. In one study, the molecular and functional characterization of S. japonicum SjMLP/HSP70 was reported. The molecule's sequence shared 77% identity with human HSP70 [mortalin-like protein (MLP)], and it was expressed widely in most developmental stages of S. japonicum (eggs, cercariae, schistosomula, and adult worms). The purified recombinant protein (rSjMLP/HSP70) was recognized by sera of infected mice. The investigators also found that the SjGST-DNA vaccine combined with SjMLP/HSP70 showed low grades of reduction (30 and 60%) of worm and egg burden in immunized mice, respectively [54] . In another study, the Chinese scientists identified in the sera of Microtus fortis, a naturally resistant vertebrate host of S. japonicum, substances with antischistosomal effects. They cloned and identified a 331 bp that was the HSP90a homologue (Mf-HSP90a). The cloned molecule showed antischistosomal effects (40-60% reduction in worm and egg burdens) both in vitro and in vivo [55] . In the third study, significant immunoprotective effects were observed when water buffalos were vaccinated with S. japonicum 23 kD membrane protein-HSP70 (SjC23-Hsp70) plus an IL-12 adjuvant. The investigators observed a reduction in all the parameters evaluated (female estrogen, fecal and hepatic egg burden) [56] .

Serodiagnosis: Four isolated HSP70 clones were evaluated for antibody activity against a panel of sera from baboons with acute and chronic schistosomiasis. The insert sizes of the four selected clones varied from 1150 to 2006 bp. It was found that antibody reactivity varied with clone length; the longest clone was the most reactive. Results suggested HSP70 immunodominance in acute as well as chronic schistosomiasis. The investigators recommended its use in the serological diagnosis of schistosomiasis mansoni [57] . Similar results were obtained on using molecules of soluble egg antigen in the diagnosis of schistosomiasis japonicum, where sera of mice with early schistosomiasis reacted with two protein molecules in soluble egg antigen: the HSP70 and 78 kDa glucose-regulated protein (Grp78/Bip) [58] . In a preliminary report, Brazilian investigators also proposed a strategy for the selection of cDNA clones that could be used in the diagnosis of schistosomiasis. Two out of five cDNA clones were identified as homologous to HSP70 [59] .

Immune response: The mechanism(s) responsible for suppression of host immune responses in chronic schistosomiasis was investigated by studying the induction of CD4 + CD25 + T cells by HSP60 of S. japonicum (SjHSP60-derived peptide; Sj MHE1). The investigators found that all mice immunized with Sj MHE1 or lymphocytes from in vitro Sj MHE1-pretreated naive mice showed an increase in CD4 + CD25 + T-cell populations as well as IL-10 and TGF-β release. The investigators suggested the possible role of TLR2 on CD4 + CD25 + induction caused by HSP60 [60] . HSP70, HSP90, and HSP97 were detected as major constituents of the proteomics profile of the excretory/secretory (E/S) products of adult S. japonicum. The investigators emphasized their central roles in immunomodulation for the host-parasite relationship [61] . In addition, Chinese scientists succeeded in cloning and constructing the recombinant plasmid of the S. japonicum HSP40 gene, which significantly initiated macrophage activation [62] .

Cancer bladder: In 2008, an Egyptian study clarified the significant association between HSP27 and HSP70 and cancer bladder caused by schistosomiasis. The investigators detected both HSPs in 60 and 68% of their patients, respectively. In addition, they found a significant correlation between HSPs expression and tumor grade and stage as well as its recurrence. They concluded that both HSPs expressions could be used as predictive biological markers for disease progression [63] .

Parasite development: Besides the morphological changes in cercaria-schistosomula transformation, cercariae have to modulate the temperature change (from external water to body temperature) and osmolarity change (from hypotonic water to saline bloodstream osmolarity). To overcome both challenges, the acetabular glands secrete HSPs as shown from the proteomic analysis of secretory products involved in host skin invasion by cercariae [64] . S. mansoni HSP70, HSP86, and HSP60 were detected in S. mansoni cercariae [65] , whereas HSP90 is a phosphoprotein detected in the different developmental stages and both sexes of S. japonicum [66] . One year later, another group of Chinese investigators emphasized the critical role of HSP in parasite development [67] . However, the heat-shock response pathway is a highly conserved and adaptive response system, and heat-shock factor 1 (Hsf1) is a major regulator of its pathway [68] . Hence, the role of gene encoding schistosomes Hsf1 in cercaria-schistosomula transformation was investigated. The results obtained confirmed the existence of Hsf1 in the cercarial stage and its expression in different schistosomal stages. The investigators identified antibodies against Hsf1 labeled on cercarial acetabular glands [69] .

Echinococcus spp.

E. granulosus : HSP70 was first reported in the serodiagnosis of hydatid cyst (HC) in 1997 in comparison with human HSP70. Both HSPs70 were assessed against patients' sera and controls. Specific antibodies' reactivity against human and parasite HSP70 was detected in 10% and 60% of the infected sera, respectively. However, 21% of the control sera reacted with E. granulosus HSP70, but the reactivity level was significantly higher in the infected patients [70] . Later, E. granulosus HSP70 was reported to stimulate the humoral and cell-mediated immune responses. Using immunoblotting, IgG, IgG4, and IgE specific to Eg2HSP70 as well as increased levels of TNF-α, interferon-g (IFN-g), IL-4, and IL-10 were detected in the sera of infected patients [71] . In addition, proteomic analysis of protoscoleces and hydatid fluid extracted from HC identified HSP20 and HSP70 [72] .

In 2010, HSP20 was identified and characterized as an immunogenic protein of E. multilocularis, and its recombinant variant showed specific reactivity to sera from infected dogs, suggesting its efficacy as a vaccine candidate [73] . One year later, also using the proteomic approach, Italian investigators succeeded in identifying HSP20 as a biological marker for the development and progression of HC. HSP20 could react with sera from HC-infected patients with different disease phases. The reaction was higher with sera from patients with active disease than in sera from patients with inactive disease [74] . Moreover, fluids from fertile HCs collected from sheep and humans as well as from infertile HCs from cattle were analyzed using tandem mass spectrometry. The investigators identified 48 proteins of parasitic origin, of which parasitic HSPs, cathepsin B and Annexin A13, were detected exclusively in infertile cysts. The investigators reported increased cellular stress and apoptosis as the major causes of their infertility [75] .

Strongyloides spp.

HSPs play a critical role in the parasite's successful establishment, its survival under stressful conditions, and its reproduction in an adverse habitat [76] . In 2009, HSB10 was characterized in Strongyloides ratti parasitic female E/S products [77] . A proteomic study of S. ratti was carried out to identify proteins found as E/S products from different developmental stages (infective larvae, parasitic females, and free-living stages). Small HSP (SrHSP10) and SrHSP60 were among the proteins abundantly observed in all the stages [78] . In the same year, another team of German investigators used mass spectrometry to identify and characterize two novel HSPs from S. ratti (SrHSP-17.1 and SrHSP-17.2) in the parasitic female E/S products. In their report, they reported the Sra-HSP-17s genomic organization, recombinant expression, purification, and antigenicity. They also showed that Sra-HSP-17s activated host cells (monocytes, macrophages, and intestinal epithelial cells), but not the lymphocytes and granulocytes. Moreover, purified rSrHSP-17s could induce IL-10 production by mononuclear cells [79] . Nouir et al. [80] from Germany worked on strongyloidiasis by analyzing the immune response to S. ratti HSP60 (SrHSP60) in infected mice. Their results showed that SrHSP60 induced Th1 response in vivo, whereas alum-precipitated srHSP60 induced Th2 response and partial protection against the challenge infection [80] . In the same year, they generated monoclonal IgM specific for srHSP60, which was used as a vaccine candidate in a mice model. Results showed a reduction in the number of the parasitic adults and migrating larvae in intestinal and disseminated strongyloidiasis [81] .

Trichinella spiralis

Levels of HSPs were used to measure stress tissue injuries caused by T. spiralis. Spanish investigators assessed HSP25, HSP60, HSP70, and HSP90 kinetics production from injured liver and muscle of infected and control mice. They found that HSP25 and HSP60 production was observed in the affected liver and infected muscles [82] . In the same year, the same investigators reported that HSP25, HSP60, and HSP70 production increased and varied in infected rat tissues (brain and spleen) according to the infection cycle, whereas a significant reduction in HSP90 was observed. The investigators did not suggest a role for HSP90 in the infection cycle [83] . However, no difference was detected in any of these HSPs in tissues of infected rats (muscle, liver, brain, and spleen) with primary trichinosis and rats reinfected 45 days after the primary infection [84] . One year later, the same investigators measured these HSPs in other infected organs (intestines, mesenteric lymph nodes, heart, and lungs) at different time points during first exposure and second reinfection. The results suggested that in reinfection, there is a sort of challenge and muscle larvae developed to adults, producing newborn larvae that were trapped in the mesenteric lymph nodes, thus increasing HSPs levels [85] . In another study, Martinez et al. [86] used three techniques to identify and purify HSPs (60, 70, and 90) from T. spiralis larvae: affinity chromatography, immunoblotting using either their monoclonal antibodies or preimmune and immune rat sera, and ELISA. Only sera from infected rats (7 days after infection) showed reactivity against the HSPs identified [86] .

A team of Egyptian scientists succeeded in obtaining HSP70 from crude somatic extracts and E/S products of adult T. spiralis, and used them to immunize mice against challenge infection. The resulting strong immunogenic reactions of HSP70 were evaluated by parasitological measures (worm and muscle larval burden) and increased total g-globulins [87] . The first molecular cloning and characterization of HSP70 from T. spiralis was performed in China. The recombinant TsHSP70 formulated with Freund's adjuvant proved to be a possible candidate vaccine against trichinosis as shown in the strong humoral immune responses in mice challenged with T. spiralis larvae [88] . Two years later, screening of cDNA libraries from T. spiralis adult worms against sera from infected pigs produced several positive clones. Of these clones, 14 showed sequence identity with HSP70, suggesting its major role in host-parasite interactions [89] .

Filarial nematodes

In lymphatic filariasis, there is impaired monocyte functions indicated by reduced production of chemokines (e.g. IL-8, eotaxin, and Exodus II), and cytokines (e.g. IL-1α, IL-12p40, IL-12p70, IFN-g, and IL-10) [90] . A group of American scientists assessed gene expression patterns of monocytes from infected patients and healthy individuals. They recorded differences in expression among the genes involved in apoptosis and cell adhesion. They further compared these gene expressions to before and after treatment (single dose of ivermectin-albendazole), and the most detected alterations were found in the expression of HSP60, HSP70, HSP90, and HSP105 genes. The investigators concluded that treatment resulted in the clearance of the parasite's antigens that retained monocyte-suppressive functions, releasing chemokines and cytokines as well as increasing HSPs expression [91] . However, it was reported that recombinant Wolbachia (microfilarial symbiotic bacteria) HSP60 (rwmHSP60) regulates immune activation in lymphatic filariasis by inhibition of secretion of proinflammatory cytokines from activated T cells through TLR signaling. Decreased CD69 with elevated CD127 and CD62L as well as IL-10 and TGF-β in infected patients confirmed reduced T-cell activation because of HSP60 stimulation [92] . One year later, Indian investigators reported that rwmHSP60 also induced proinflammatory cytokine production (IL-1β, IL-6, and TNF-α), reduced phagocytic function of monocyte/macrophage, and promoted apoptosis of human monocytes [93] .

Wuchereria bancrofti and Brugia spp.: Brugia spp. (malayi and pahangi) HSP70 was first discovered in 1987, and was described as a protein expressed in both the insect and host parasitic stages. The investigators reported that it played no role in host immune response [94] . At the same time, they used the C-terminal portion of Brugia spp. HSP70 (Bpa-26) as an indicator for chronic Brugian filariasis. The investigators found significantly higher IgG3 levels in chronic patients compared with microfilaremic and asymptomatic amicrofilaremic patients [95] . The recombinant protein of Brugia malayi Wolbachia HSP60 was also reported to generate antibody response (total IgG and Ig1) in all individuals from an area endemic for W. bancrofti [96] . In 2010, HSP70 identified from the bovine filarial parasite Setaria cervi showed 98% identity with that of W. bancrofti and only 28% with human HSP70 [97] .

The specific inhibitor of B. pahangi HSP90 such as geldanamycin was reported to kill adult worms and microfilariae in vitro. However, it proved to have severe hepatotoxic hazards besides being metabolically and chemically unstable [98] . One year later, the same investigators developed a fluorescence polarization assay that proved sensitive and specific in identifying new compounds that bind to the HSP90 pocket and could be used as an HSP90 specific inhibitor. The investigators validated their assay and its adaptation to screen HSP90 inhibitors against other parasites [99] . In a study carried out by American and Indian investigators, the vaccine potential of B. malayi HSP12.6 (BmHSP12.6) was evaluated in infected mice. The results showed that vaccinated mice had ~72% protection against the challenge infection. The investigators suggested that BmHSP12.6 had host immunomodulatory functions that might interfere with microfilaria establishment in the host. Moreover, there was a significant increase in IgG1 and IgG2a antibody responses. They concluded that BmHSP12.6 could be developed into a vaccine candidate against B. malayi [100] . One year later, BmHSP12.6 was used as a partner in a trivalent fusion vaccine, and conferred significant prophylactic protection (95%) against challenge infection [101] . Recently, B. malayi HSP12.6 (which is an a crystalline domain and c-terminal extension) was included in a vaccine with a B. malayi abundant larval transcript (rBmALT-2) and a B. malayi tetraspanin large extracellular loop (rBmTSP LEL) to form rBmHATαc [102] . It conferred 68% protection in mice with challenge infection that increased to more than 95% protection when AL007 (alum from IDRI) or AL019 (alum plus TLR-4 agonist from IDRI) was used as an adjuvant [103] . More recently, German scientists investigated the role of B. malayi HSP70 in immunizing BALB/c mice against challenge infection with Litomosoides sigmodontis (rodent filarial worm). The results indicated reduced numbers of pleural cavity larvae and circulating microfilariae as well as increased production of type I and II cytokines. The investigators concluded its potential role as a vaccine candidate [104] .

Onchocerca volvulus: HSP70 was first reported in 1989 when investigators recognized three cloned filarial immunogenic antigens that reacted with sera from infected patients. One of these immunogenic antigens recognized by amicrofilaremic patients is an O. volvulus protein homologous to the 70 kDa HSP of the African frog Xenopus laevis [105] . Later, chaperonin 60 (CPN60) or HSP60 of O. volvulus (OvCPN60) was reported in 2000 and the investigators detected it in all life-cycle stages. Antibodies raised against OvCPN60 were found in ~90% of infected patients in West Africa [106] . In 2008, a group of German scientists reported that killing Wolbachia bacteria in O. volvulus-infected patients resulted in an increase in HSP60 production from filarial mitochondria. To differentiate between HSP60 from Wolbachia and that of filarial mitochondria, they used antiserum raised against HSP60 to specifically bind to the protein and stain it in both Wolbachia and mitochondria. They attributed this increased expression to homeostasis disruption of endosymbiosis [107] .

Other helminthes

Taenia solium: A small HSP, Tsol-sfISP35.6, was isolated by antibody screening of a T. solium cDNA library, followed by cloning. Using western blot analysis and ELISA, the clone reacted with 80% of sera of infected pigs, 84% of patients with active neurocysticercosis, and 71% of patients with inactive diseases [108] .

Echinostoma spp.: Using a proteomic approach, Spanish investigators identified protein spots corresponding to 10 proteins including HSP70 in E. friedi E/S products. The stress protein showed variable expression patterns in chronic and acute infections in experimentally infected rodents, suggesting its role in parasite survival [109] . HSP70 was also identified in E. caproni E/S products. Another group of Spanish investigators recognized an early IgM response generated by HSP70, suggesting its importance in parasite establishment because of its early exposure to the host immune response. Moreover, IgA response was mediated by HSP70, which was attributed to its close contact with the host mucosal surface [110] .

Paragonimus westermani: In 2007, the P. westermani egg antigen gene was cloned and evaluated as an antigen for the serological diagnosis of paragonimiasis. Using ELISA against sera from patients infected with different parasites (including patients with paragonimiasis) and negative controls, its sensitivity and specificity were 90.2 and 100%, respectively. Moreover, its sequence was 40, 38, and 35% identical to HSPs from S. japonicum, S. mansoni, and T. saginata, respectively [111] .

Fasciola spp.: In 2008, F. hepatica and F. gigantica HSP70s were cloned and characterized. Using Western blot analysis, Australian investigators found 98-99% identity in their protein sequences. However, the 70 kD protein was not detected in the parasite E/S products. Analysis of HSP70 expression in fascioliasisaffecting sheep (not cattle), showed higher HSP70 expression in F. gigantica than F. hepatica. This result highlighted the importance of HSP70 as a biochemical marker of F. gigantica stress response [112] .

Clonorchis sinensis: In clonorchiasis, HSP27, HSP90 expressions as well as levels of inflammatory cytokines (IL-1β, IL-2, TGF-β2, and IFN-α1) were increased in infected hamsters compared to control group. This significant increase was correlated with the severity of bile duct hyperplasia, liver fibrosis, and hepatic necrosis [113] .

  Concluding remarks Top

  1. HSPs play important roles in the correction of cell protein functions under stress conditions and share in several immunological processes of innate and adaptive immunity. Their role in the vaccination era was reported against cancer (such as cancer colon, renal cell carcinoma, and pancreatic adenocarcinoma) as well as against microbial and parasitic diseases. HSPs expression was also found to be directed against apoptosis, especially in intracellular protozoon.
  2. Several studies were carried out using HSP70 as a vaccine candidate in schistosomiasis japonicum. In addition, few studies suggested the use of HSP70 in the serological diagnosis of schistosomiasis mansoni.
  3. HSP70 and HSP90 were detected as major constituents of the proteomics profile of the E/S products of adult S. japonicum, and they were impacted in host-parasite relationship immunomodulation. However, HSP70, HSP86, and HSP60 were detected in the secretory products of S. mansoni cercariae, and they play a critical role in parasite development.
  4. In hydatid disease, E. granulosus HSP70 was observed as an immunogenic protein stimulating both the humoral and the cell-mediated immune responses. Use of E. multilocularis HSP20 was suggested as a vaccine candidate.
  5. In strongyloidiasis, small HSP (HSP10) and HSP60 were observed in all the stages of S. ratti. Other sHSPs (HSP17) were detected in the parasitic female E/S products, which activated most host cells and induced IL-10. However, HSP70 was found to induce Th1 response in vivo, suggesting its use in protection against challenge infection.
  6. Several HSPs were reported to be increased during stress tissue injuries in trichinosis such as HSP25, HSP60, and HSP70. There is some contradiction on HSP90 production from the injured tissues. However, HSPs 60, 70, and 90 from T. spiralis larvae showed reactivity against sera from T. spiralis-infected rats.
  7. T. spiralis HSP70 produced strong immunogenic reactions when used to immunize mice against challenge infection.
  8. HSP70 of both W. bancrofti and Brugia spp. were recognized as immunogenic proteins capable of significant production of IgG3 levels. In addition, B. malayi HSP70 was used to immunize mice and showed its potential role as a vaccine candidate. However, B. malayi HSP12.6 was used as a partner in a trivalent fusion vaccine (rBmHATαc), which conferred excellent protection in mice if used with AL007 or AL019 as adjuvants.
  9. Few other studies have focused on HSPs in other diseases caused by helminths, for example O. volvulus, in which HSP60 was detected in all life-cycle stages. A clone of HSP 35.6 in T. solium reacted with the majority of sera from patients with active neurocysticercosis. HSP70 was detected in different Echinostoma spp., and it was found that IgA response was mediated by HSP70. In fascioliasis, HSP70 showed high potentiality as a biochemical marker in infection with F. gigantica. In clonorchiasis, HSP27 and HSP90 expressions were elevated with increased production of inflammatory cytokines.

  Acknowledgements Top

Conflicts of interest

There are no conflicts of interest.

  References Top

Lindquist S, Craig EA. The heat-shock proteins. Ann Rev Genet 1988; 22:631-677.  Back to cited text no. 1
Ritossa F. A new puffing pattern induced by temperature shock and DNP in Drosophila. Experientia 1962; 18:571-573.  Back to cited text no. 2
Lindquist S. The heat-shock response. Ann Rev Biochem 1986; 55: 1151-1191.  Back to cited text no. 3
Parsell DA, Lindquist S. The function of heat-shock proteins in stress tolerance: degradation and reactivation of damaged proteins. Ann Rev Genet 1993; 27:437-496.  Back to cited text no. 4
Srivastava P. Interaction of heat shock proteins with peptides and antigen presenting cells: chaperoning of the innate and adaptive immune responses. Ann Rev Immunol 2002a; 20:395-425.  Back to cited text no. 5
Rajaiah R, Moudgil KD. Heat-shock proteins can promote as well as regulate autoimmunity. Autoimmun Rev 2009; 8:388-393.  Back to cited text no. 6
Kampinga HH, Hageman J, Vos MJ, et al. Guidelines for the nomenclature of the human heat shock proteins. Cell Stress Chaperones 2009; 14: 105-111.  Back to cited text no. 7
Young JC, Agashe VR, Siegers K, Hartl FU. Pathways of chaperone-mediated protein folding in the cytosol. Nat Rev Mol Cell Biol 2004; 5: 781-791.  Back to cited text no. 8
Pearl LH, Prodromou C. Structure and mechanism of the Hsp90 molecular chaperone machinery. Ann Rev Biochem 2006; 75:271-294.  Back to cited text no. 9
Kress W, Maglica Z, Weber-Ban E. Clp chaperone-proteases: structure and function. Res Microbiol 2009; 160:618-628.  Back to cited text no. 10
Kiang JG, Tsokos GC. Heat shock protein 70 kDa: molecular biology, biochemistry and physiology. Pharmacol Ther 1998; 80:183-201.  Back to cited text no. 11
Asea A, Kraeft SK, Kurt-Jones EA, et al. HSP70 stimulates cytokine production through a CD14-dependant pathway, demonstrating its dual role as a chaperone and cytokine. Nat Med 2000; 6:435-442.  Back to cited text no. 12
Wang Y, Kelly CG, Singh M, et al. Stimulation of Th1-polarizing cytokines, C-C chemokines, maturation of dendritic cells, and adjuvant function by the peptide binding fragment of heat shock protein 70. J Immunol 2002; 169:2422-2429.  Back to cited text no. 13
Wan T, Zhou X, Chen G, et al. Novel heat shock protein Hsp70L1 activates dendritic cells and acts as a Th1 polarizing adjuvant. Blood 2004, 103:1747-1754.  Back to cited text no. 14
Shoenfeld Y, Harats D, George J. Heat shock protein 60/65, β2-glycoprotein I and oxidized LDL as players in murine atherosclerosis. J Autoimmun 2000; 15:199-202.  Back to cited text no. 15
Huurman VAL, van der Meide PE, Duinkerken G, et al. Immunological efficacy of heat shock protein 60 peptide DiaPep277 therapy in clinical type I diabetes. Clin Exp Immunol 2008; 152:488-497.  Back to cited text no. 16
Shukla HD, Pitha PM. Role of hsp90 in systemic lupus erythematosus and its clinical relevance. Autoimmune Dis 2012; 2012:728605.  Back to cited text no. 17
Direskeneli H. Innate and adaptive responses to heat shock proteins in Behcet's disease. Genet Res Int 2013; 2013:249157.  Back to cited text no. 18
Calderwood SK, Ciocca DR. Heat shock proteins: stress proteins with Janus-like properties in cancer. Inter J Hyperthermia 2008; 24:31-39.  Back to cited text no. 19
Binder RJ, Srivastava PK. Peptides chaperoned by heat-shock proteins are a necessary and sufficient source of antigen in the cross-priming of CD8+ T cells. Nat Immunol 2005; 6:593-599.  Back to cited text no. 20
Colaco CA, Bailey CR, Walker KB, Keeble J. Heat shock proteins: stimulators of innate and acquired immunity. Bio Med Res Int 2013; 2013:461230,   Back to cited text no. 21
Van Herwijnen MJ, Wieten L, van der Zee R, et al. Regulatory T cells that recognize a ubiquitous stress-inducible self-antigen are long-lived suppressors of autoimmune arthritis. Proc Natl Acad Sci USA 2012; 109:14134-14139.  Back to cited text no. 22
Suzue K, Zhou X, Eisen HN, Young RA. Heat shock fusion proteins as vehicles for antigen delivery into the major histocompatibility complex class I presentation pathway. Proc Natl Acad Sci USA 1997; 94: 13146-13151.  Back to cited text no. 23
Osterloh A, Breloer M. Heat shock proteins: linking danger and pathogen recognition. Med Microbiol Immunol 2008; 197:1-8.  Back to cited text no. 24
Shonhai A, Maier AG, Przyborski JM, Blatch GL. Intracellular protozoan parasites of humans: the role of molecular chaperones in development and pathogenesis. Protein Pept Lett 2011; 18:143-157.  Back to cited text no. 25
Roy N, Nageshan RK, Ranade S, Tatu U. Heat shock protein 90 from neglected protozoan parasites. Biochim Biophys Acta 2012; 1823: 707-711.  Back to cited text no. 26
Rochani AK, Singh M, Tatu U. Heat shock protein 90 inhibitors as broad spectrum anti-infectives. Curr Pharm Des 2013; 19:377-386.  Back to cited text no. 27
Macario AJ. Heat-shock proteins and molecular chaperones: Implications for pathogenesis, diagnostics and therapeutics. Int J Clin Lab Res 1995; 25:59-70.  Back to cited text no. 28
Basu S, Binder RJ, Suto R, Anderson KM, Srivastava PK. Necrotic but not apoptotic cell death releases heat shock proteins, which deliver a partial maturation signal to dendritic cells and activate the NF-kB pathway. Int Immunol 2000; 12:1539-1546.  Back to cited text no. 29
Merendino AM, Bucchieri F, Campanella C, et al. Hsp60 is actively secreted by human tumor cells. PLoS ONE 2010; 5:e9247.  Back to cited text no. 30
Friedland JS, Shattock R, Remick DG, Griffin GE. Mycobacterial 65-kD heat shock protein induces release of proinflammatory cytokines from human monocytic cells. Clin Exp Immunol 1993; 91:58-62.  Back to cited text no. 31
Wang Y, Whittall T, McGowan E, et al. Identification of stimulating and inhibitory epitopes within the heat shock protein 70 molecule that modulate cytokine production and maturation of dendritic cells. J Immunol 2005; 174:3306-3316.  Back to cited text no. 32
Panayi GS, Corrigall VM. BiP regulates autoimmune inflammation and tissue damage. Autoimmun Rev 2006; 5:140-142.  Back to cited text no. 33
Li Z, Srivastava PK. Tumor rejection antigen gp96/grp94 is an ATPase: implications for protein folding and antigen presentation. EMBO J 1993; 12:3143-3151.  Back to cited text no. 34
Srivastava P. Roles of heat-shock proteins in innate and adaptive immunity. Nat Rev Immunol 2002b; 2:185-194.  Back to cited text no. 35
Dollins DE, Warren JJ, Immormino RM, Gewirth DT. Structures of grp94-nucleotide complexes reveal mechanistic differences between the hsp90 chaperones. Mol Cell 2007; 28:41-56.  Back to cited text no. 36
Castellino F, Boucher PE, Eichelberg K, et al. Receptor-mediated uptake of antigen/heat shock protein complexes results in major histocompatibility complex class I antigen presentation via two distinct processing pathways. J Exp Med 2000; 191:1957-1964.  Back to cited text no. 37
Ichiyanagi T, Imai T, Kajiwara C, et al. Essential role of endogenous heat shock protein 90 of dendritic cells in antigen cross-presentation. J Immunol 2010; 185:2693-2700.  Back to cited text no. 38
Janetzki S, Palla D, Rosenhauer V, Lochs H, Lewis JJ, Srivastava P. Immunization of cancer patients with autologous cancer-derived heat shock protein gp96 reparations: a pilot study. Int J Cancer 2000; 88: 232-238.  Back to cited text no. 39
Reitsma DJ, Combest AJ. Challenges in the development of an autologous heat shock protein based anti-tumor vaccine. Hum Vaccin Immunother 2012; 8:1152-1155.  Back to cited text no. 40
Wood C, Srivastava P, Bukowski R, et al. An adjuvant autologous therapeutic vaccine (HSPPC-96; vitespen) versus observation alone for patients at high risk of recurrence after nephrectomy for renal cell carcinoma: a multicentre, open-label, randomized phase III trial. Lancet 2008; 372:145-154.  Back to cited text no. 41
Colaco C. Autologous heat-shock protein vaccines. Hum Vaccin Immunother 2013; 9:1-2.  Back to cited text no. 42
Peetermans WE, Langermans JAM, van der Hulst MEB, van Embden JDA, van Furth R. Murine peritoneal macrophages activated by the mycobacterial 65- kilodalton heat shock protein express enhanced microbicidal activity in vitro. Infect Immun 1993; 61:868-875.  Back to cited text no. 43
Silva CL, Silva MF, Pietro RCLR, Lowrie DB. Characterization of T cells that confer a high degree of protective immunity against tuberculosis in mice after vaccination with tumor cells expressing mycobacterial hsp65. Infect Immun 1996; 64:2400-2407.  Back to cited text no. 44
Lowrie DB, Tascon RE, Colston MJ, Silva C.L Towards a DNA vaccine against tuberculosis. Vaccine 1994; 12:1537-1540.  Back to cited text no. 45
Tascon RE, Colston MJ, Ragno S, Stavropoulos E, Gregory D, Lowrie DB. Vaccination against tuberculosis by DNA injection. Nat Med 1996; 2: 888-892.  Back to cited text no. 46
Taylor JL, Ordway DJ, Troudt J, Gonzalez-Juarrero M, Basaraba RJ, Orme IM. Factors associated with severe granulomatous pneumonia in Mycobacterium tuberculosis-infected mice vaccinated therapeutically with hsp65 DNA. Infect Immun 2005; 73:5189-5193.  Back to cited text no. 47
Taylor JL, Wieczorek A, Keyser AR, et al. HspX-mediated protection against tuberculosis depends on its chaperoning of a mycobacterial molecule. Immunol Cell Biol 2012; 90:945-954.  Back to cited text no. 48
Heussler VT, Küenzi P, Rottenberg S. Inhibition of apoptosis by intracellular protozoan parasites. Int J Parasitol 2001; 31:1166-1176.  Back to cited text no. 49
Neumann S, Ziv E, Lantner F, Schechter I. Regulation of HSP70 gene expression during the life cycle of the parasitic helminth Schistosoma mansoni. Eur J Biochem 1993; 212:589-596.  Back to cited text no. 50
Richter D, Reynolds SR, Harn DA. Candidate vaccine antigens that stimulate the cellular immune response of mice vaccinated with irradiated cercariae of Schistosoma mansoni. J Immunol 1993; 151:256-265.  Back to cited text no. 51
Yu XL, He YK, Xiong T, et al. Protective effects of co-immunization with SjCTPI-Hsp70 and interleukin-12 DNA vaccines against Schistosoma japonicum challenge infection in water buffalo [in Chinese]. Zhongguo Ji Sheng Chong Xue Yu Ji Sheng Chong Bing Za Zhi 2006; 24:433-436.   Back to cited text no. 52
Da'Dara AA, Li YS, Xiong T, et al. DNA-based vaccines protect against zoonotic schistosomiasis in water buffalo. Vaccine 2008; 26:3617-3625.  Back to cited text no. 53
He S, Yang L, Lv Z, et al. Molecular and functional characterization of a mortalin-like protein from Schistosoma japonicum (SjMLP/hsp70) as a member of the HSP70 family. Parasitol Res 2010; 107:955-966.  Back to cited text no. 54
Gong Q, Cheng G, Qin ZQ, Xiong DH, Yu YJ, Zeng QR, Hu WX. Identification of the resistance of a novel molecule heat shock protein 90alpha (HSP90alpha) in Microtus fortis to Schistosoma japonicum infection. Acta Trop 2010; 115:220-226.  Back to cited text no. 55
Hu P, Xia D, Cui H, et al. Protective effect of SjC23-Hsp70 DNA vaccine and interleukin-12 on Schistosoma japonicum infection in water buffalos. Zhong Nan Da Xue Xue Bao Yi Xue Ban [in Chinese] 2012; 37:854-859.   Back to cited text no. 56
Kanamura HY, Hancock K, Rodrigues V, Damian RT. Schistosoma mansoni heat shock protein 70 elicits an early humoral immune response in S. mansoni infected baboons. Mem Inst Oswaldo Cruz 2002; 97: 711-716.  Back to cited text no. 57
Wang J, Song LJ, He W, et al. Identification of early diagnostic molecules in soluble egg antigen of Schistosoma japonicum by MASS [in Chinese]. Zhongguo Xue Xi Chong Bing Fang Zhi Za Zhi 2012; 24:132-136.   Back to cited text no. 58
Valli LCP, Kanamura HY, Cotrim PC, Oliveira GC, de Oliveira EJ. Characterization of a clone from an adult worm cDNA library selected with anti-Schistosoma mansoni human antibodies dissociated from immune complexes: a preliminary report. Rev Inst Med Trop Sao Paulo 2007; 49:187-189.  Back to cited text no. 59
Wang X, Zhou S, Chi Y, et al. CD4+CD25+ Treg induction by an HSP60-derived peptide SJMHE1 from Schistosoma japonicum is TLR2 dependent. Eur J Immunol 2009; 39:3052-3065.  Back to cited text no. 60
Liu F, Cui SJ, Hu W, Feng Z, Wang ZQ, Guang ZQ, Han ZG. Excretory/secretory proteome of the adult developmental stage of human blood fluke, Schistosoma japonicum. Mol Cell Proteomics 2009; 8:1236-1251.  Back to cited text no. 61
Li SS, Xu XT, Liu W, et al. Effects of Schistosoma japonicum heat-shock protein 40 on macrophage activation [in Chinese]. Zhongguo Xue Xi Chong Bing Fang Zhi Za Zhi 2012; 24:137-141,   Back to cited text no. 62
El-Kenawy EA, El-Kott AF, Hasan MS. Heat shock protein expression independently predicts survival outcome in schistosomiasis-associated urinary bladder cancer. Int J Biol Markers 2008; 23:214-218.  Back to cited text no. 63
Hansell E, Braschi S, Medzihradszky KF, et al. Proteomic analysis of skin invasion by blood fluke larvae. PLoS Negl Trop Dis 2008; 2:e262.  Back to cited text no. 64
Knudsen GM, Medzihradszky KF, Lim KC, Hansell E, McKerrow JH. Proteomic analysis of Schistosoma mansoni cercarial secretions. Mol Cell Proteomics 2005; 4:1862-1875.  Back to cited text no. 65
Luo R, Zhou C, Lin J, Yang D, Shi Y, Cheng G. Identification of in vivo protein phosphorylation sites in human pathogen Schistosoma japonicum by a phosphoproteomic approach. J Proteomics 2012; 75:868-877.  Back to cited text no. 66
Cheng G, Luo R, Hu C, et al. TiO 2 -based phosphoproteomic analysis of schistosomes: characterization of phosphorylated proteins in the different stages and sex of Schistosoma japonicum. J Proteome Res 2013; 12:729-742.  Back to cited text no. 67
Anckar J, Sistonen L. Regulation of HSF1 function in the heat stress response: implications in aging and disease. Annu Rev Biochem 2011; 80:1089-1115.  Back to cited text no. 68
Ishida K, Varrecchia M, Knudsen GM, Jolly ER. Immunolocalization of anti-hsf1 to the acetabular glands of infectious schistosomes suggests a non-transcriptional function for this transcriptional activator. PLoS Negl Trop Dis 2014; 8:e3051.  Back to cited text no. 69
Colebrook AL, Lightowlers MW. Serological reactivity to heat shock protein 70 in patients with hydatid disease. Parasite Immunol 1997; 19:41-46.  Back to cited text no. 70
Ortona E, Margutti P, Delunardo F, et al. Molecular and immunological characterization of the C-terminal region of a new Echinococcus granulosus heat shock protein 70. Parasite Immunol 2003; 25:119-126.  Back to cited text no. 71
Chemale G, van Rossum AJ, Jefferies JR, et al. Proteomic analysis of the larval stage of the parasite Echinococcus granulosus: causative agent of cystic hydatid disease. Proteomics 2003; 3:1633-1636.  Back to cited text no. 72
Kouguchi H, Matsumoto J, Katoh Y, Suzuki T, Oku Y, Yagi K. Echinococcus multilocularis: two-dimensional Western blotting method for the identification and expression analysis of immunogenic proteins in infected dogs. Exp Parasitol 2010; 124:238-243.  Back to cited text no. 73
Vacirca D, Perdicchio M, Campisi E, et al. Favorable prognostic value of antibodies anti-HSP20 in patients with cystic echinococcosis: a differential immunoproteomic approach. Parasite Immunol 2011; 33:193-198.  Back to cited text no. 74
Aziz A, Zhang W, Li J, Loukas A, McManus DP, Mulvenna J. Proteomic characterization of Echinococcus granulosus hydatid cyst fluid from sheep, cattle and humans. J Proteomics 2011; 74:1560-1572.  Back to cited text no. 75
Morimoto RI. Regulation of the heat shock transcriptional response: cross talk between a family of heat shock factors, molecular chaperones, and negative regulators. Genes Dev 1998; 12:3788-3796.  Back to cited text no. 76
Tazir Y, Steisslinger V, Soblik H, et al. Molecular and functional characterization of the heat shock protein 10 of Strongyloides ratti. Mol Biochem Parasitol 2009; 168:149-157.  Back to cited text no. 77
Soblik H, Younis AE, Mitreva M, et al. Life cycle stage-resolved proteomic analysis of the excretome/secretome from Strongyloides ratti: identification of stage-specific proteases. Mol Cell Proteomics 2011; 10:M111.010157.  Back to cited text no. 78
Younis AE, Geisinger F, Ajonina-Ekoti I, et al. Stage-specific excretory-secretory small heat shock proteins from the parasitic nematode Strongyloides ratti: putative links to host's intestinal mucosal defense system. FEBS J 2011; 278:3319-3336.  Back to cited text no. 79
Nouir NB, Eschbach ML, Piédavent M, et al. Vaccination with Strongyloides ratti heat shock protein 60 increases susceptibility to challenge infection by induction of Th1 response. Vaccine 2012a; 30:862-871.  Back to cited text no. 80
Nouir NB, Piédavent M, Osterloh A, Breloer M. Passive immunization with a monoclonal IgM antibody specific for Strongyloides ratti HSP60 protects mice against challenge infection. Vaccine 2012b; 30: 4971-4976.  Back to cited text no. 81
Martinez J, Perez Serrano J, Bernadina WE, Rodriguez-Caabeiro F. Influence of parasitization by Trichinella spiralis on the levels of heat shock proteins in rat liver and muscle. Parasitology 1999a; 118:201-209.  Back to cited text no. 82
Martinez J, Perez-Serrano J, Bernadina WE, Rodriguez-Caabeiro F. Shock response induced in rat brain and spleen during primary infection with Trichinella spiralis larvae. Parasitology 1999b; 118:605-613.  Back to cited text no. 83
Martinez J, Perez-Serrano J, Bernadina WE, Rodriguez-Caabeiro F. Using heat shock proteins as indicators of the immune function in wistar rats during a secondary Trichinella spiralis infection. Vet Parasitol 1999; 85:269-275.  Back to cited text no. 84
Pérez-Serrano J, Martínez J, Regal P, Bernadina WE, Rodríguez-Caabeiro F. Prior immunity to Trichinella spiralis prevents (re)occurrence of an explicit stress response in intestines but not in mesenteric lymph nodes, heart and lungs from reinfected rats. Parasitology 2000; 121: 565-573.  Back to cited text no. 85
Martinez J, Pérez-Serrano J, Bernadina WE, Rodríguez-Caabeiro F. HSP60, HSP70 and HSP90 from Trichinella spiralis as targets of humoral immune response in rats. Parasitol Res 2001; 87:453-458.  Back to cited text no. 86
Salem SA, El-Kowrany SI, Ismail HI, El-Sheikh TF. Study on the possible role of heat shock proteins in host resistance to Trichinella spiralis infection in experimental animals. J Egypt Soc Parasitol 2001; 31: 133-144.  Back to cited text no. 87
Wang S, Zhu X, Yang Y, et al. Molecular cloning and characterization of heat shock protein 70 from Trichinella spiralis. Acta Trop 2009; 110: 46-51.  Back to cited text no. 88
Zocevic A, Mace P, Vallee I, et al. Identification of Trichinella spiralis early antigens at the pre-adult and adult stages. Parasitology 2011; 138:463-471.  Back to cited text no. 89
Semnani RT, Liu AY, Sabzevari H, et al. Brugia malayi microfilariae induce cell death in human dendritic cells, inhibit their ability to make IL-12 and IL-10, and reduce their capacity to activate CD4 + T cells. J Immunol 2003; 171:1950-1960.  Back to cited text no. 90
Semnani RT, Keiser PB, Coulibaly YI, et al. Filaria-induced monocyte dysfunction and its reversal following treatment. Infect Immun 2006; 74:4409-4417.  Back to cited text no. 91
Shiny C, Krushna NS, Babu S, Elango S, Manokaran G, Narayanan RB Recombinant Wolbachia heat shock protein 60 (HSP60) mediated immune responses in patients with lymphatic filariasis. Microbes Infect 2011; 13:1221-1231.  Back to cited text no. 92
Kamalakannan V, Kirthika S, Haripriya K, Babu S, Narayanan RB Wolbachia heat shock protein 60 induces pro-inflammatory cytokines and apoptosis in monocytes in vitro. Microbes Infect 2012; 14:610-618.  Back to cited text no. 93
Selkirk ME, Rutherford PJ, Denham Da, Partono F, Maizels RM. Cloned antigen genes of Brugia filarial parasites. Biochem Soc Symp 1987; 53:91-102.  Back to cited text no. 94
Yazdanbakhsh M, Paxton WA, Brandenburg A, et al. Differential antibody isotype reactivity to specific antigens in human lymphatic filariasis: gp15/400 preferentially induces immunoglobulin E (IgE), IgG4, and IgG2. Infect Immun 1995; 63:3772-3779.  Back to cited text no. 95
Suba N, Shiny C, Taylor MJ, Narayanan RB Brugia malayi Wolbachia hsp60 IgG antibody and isotype reactivity in different clinical groups infected or exposed to human bancroftian lymphatic filariasis. Exp Parasitol 2007; 116:291-295.  Back to cited text no. 96
Srivastava S, Srikanth E, Liebau E, Rathaur S. Identification of Setaria cervi heat shock protein 70 by mass spectrometry and its evaluation as diagnostic marker for lymphatic filariasis. Vaccine 2010; 28: 1429-1436.  Back to cited text no. 97
Taldone T, Sun W, Chiosis G Discovery and development of heat shock protein 90 inhibitors. Bioorg Med Chem 2009; 17:2225-2235.  Back to cited text no. 98
Taldone T, Gillan V, Sun W, et al. Assay strategies for the discovery and validation of therapeutics targeting Brugia pahangi Hsp90. PLoS Negl Trop Dis 2010; 4:e714.  Back to cited text no. 99
Dakshinamoorthy G, Samykutty AK, Munirathinam G, et al. Biochemical characterization and evaluation of a Brugia malayi small heat shock protein as a vaccine against lymphatic filariasis. PLoS One 2012; 7:e34077.  Back to cited text no. 100
Dakshinamoorthy G, Samykutty AK, Munirathinam G, Reddy MV, Kalyanasundaram R Multivalent fusion protein vaccine for lymphatic filariasis. Vaccine 2013; 31:1616-1622.  Back to cited text no. 101
Joseph SK, Ramaswamy K. Single multivalent vaccination boosted by trickle larval infection confers protection against experimental lymphatic filariasis. Vaccine 2013; 31:3320-3326.  Back to cited text no. 102
Dakshinamoorthy G, Kalyanasundaram R. Evaluating the efficacy of rBmHATαc as a multivalent vaccine against lymphatic filariasis in experimental animals and optimizing the adjuvant formulation. Vaccine 2013; 32:19-25.  Back to cited text no. 103
Hartmann W, Singh N, Rathaur S, et al. Immunization with Brugia malayi Hsp70 protects mice against Litomosoides sigmodontis challenge infection. Parasite Immunol 2014; 36:141-149.  Back to cited text no. 104
Rothstein NM, Higashi G, Yates J, Rajan TV. Onchocerca volvulus heat shock protein 70 is a major immunogen in amicrofilaremic individuals from a filariasis-endemic area. Mol Biochem Parasitol 1989; 33:229-235.  Back to cited text no. 105
Wu Y, Egerton G, Ball A, Tanguay RM, Bianco AE Characterization of the heat-shock protein 60 chaperonin from Onchocerca volvulus. Mol Biochem Parasitol 2000; 107:155-168.  Back to cited text no. 106
Pfarr KM, Heider U, Schmetz C, Büttner DW, Hoerauf A. The mitochondrial heat shock protein 60 (HSP60) is up-regulated in Onchocerca volvulus after the depletion of Wolbachia. Parasitology 2008; 135:529-538.  Back to cited text no. 107
Ferrer E, González LM, Foster-Cuevas M, et al. Taenia solium: characterization of a small heat shock protein (Tsol-sHSP35.6) and its possible relevance to the diagnosis and pathogenesis of neurocysticercosis. Exp Parasitol 2005; 110:1-11.  Back to cited text no. 108
Bernal D, Carpena I, Espert AM, et al. Identification of proteins in excretory/secretory extracts of Echinostoma friedi (Trematoda) from chronic and acute infections. Proteomics 2006; 6:2835-2843.  Back to cited text no. 109
Sotillo J, Valero L, Sánchez Del Pino MM, et al. Identification of antigenic proteins from Echinostoma caproni (Trematoda) recognized by mouse immunoglobulins M, A and G using an immunoproteomic approach. Parasite Immunol 2008; 30:271-279.  Back to cited text no. 110
Lee JS, Lee J, Kim SH, Yong TS. Molecular cloning and characterization of a major egg antigen in Paragonimus westermani and its use in ELISA for the immunodiagnosis of paragonimiasis. Parasitol Res 2007; 100:677-681.  Back to cited text no. 111
Smith RE, Spithill TW, Pike RN, Meeusen EN, Piedrafita D. Fasciola hepatica and Fasciola gigantica: cloning and characterisation of 70 kDa heat-shock proteins reveals variation in HSP70 gene expression between parasite species recovered from sheep. Exp Parasitol 2008; 118:536-542.  Back to cited text no. 112
Choi W, Chu J. The characteristics of the expression of heat shock proteins and COX-2 in the liver of hamsters infected with Clonorchis sinensis, and the change of endocrine hormones and cytokines. Folia Parasitol (Praha) 2012; 59:255-263.  Back to cited text no. 113

This article has been cited by
1 A first attempt at determining the antibody-specific pattern of Platynosomum fastosum crude antigen and identification of immunoreactive proteins for immunodiagnosis of feline platynosomiasis
Babi Kyi Soe, Poom Adisakwattana, Onrapak Reamtong, Panat Anuracpreeda, Woraporn Sukhumavasi
Veterinary World. 2022; : 2029
[Pubmed] | [DOI]
2 Effects of Multispecies Probiotic on Intestinal Microbiota and Mucosal Barrier Function of Neonatal Calves Infected With E. coli K99
Yanyan Wu, Cunxi Nie, Ruiqing Luo, Fenghua Qi, Xue Bai, Hongli Chen, Junli Niu, Chen Chen, Wenju Zhang
Frontiers in Microbiology. 2022; 12
[Pubmed] | [DOI]
3 Liver Proteome Alterations in Red Deer (Cervus elaphus) Infected by the Giant Liver Fluke Fascioloides magna
Karol Šimonji, Dean Konjevic, Miljenko Bujanic, Ivana Rubic, Vladimir Farkaš, Andelo Beletic, Lea Grbavac, Josipa Kuleš
Pathogens. 2022; 11(12): 1503
[Pubmed] | [DOI]
4 Proteins as Targets in Anti-Schistosomal Drug Discovery and Vaccine Development
Ndibonani Kebonang Qokoyi,Priscilla Masamba,Abidemi Paul Kappo
Vaccines. 2021; 9(7): 762
[Pubmed] | [DOI]
5 Complementary liver and serum protein profile in wild boars infected by the giant liver fluke Fascioloides magna using tandem mass tags quantitative approach
Josipa Kuleš,Lea Lovric,Andrea Gelemanovic,Blanka Beer Ljubic,Ivana Rubic,Miljenko Bujanic,Dean Konjevic
Journal of Proteomics. 2021; 247: 104332
[Pubmed] | [DOI]
6 Fate of Ascaris at various pH, temperature and moisture levels
Jenna Senecal,Annika Nordin,Björn Vinnerĺs
Journal of Water and Health. 2020;
[Pubmed] | [DOI]
7 Heat shock proteins in infection
Azam Bolhassani,Elnaz Agi
Clinica Chimica Acta. 2019; 498: 90
[Pubmed] | [DOI]


Similar in PUBMED
   Search Pubmed for
   Search in Google Scholar for
 Related articles
Access Statistics
Email Alert *
Add to My List *
* Registration required (free)

  In this article
Concluding remarks

 Article Access Statistics
    PDF Downloaded398    
    Comments [Add]    
    Cited by others 7    

Recommend this journal