Filarial Immunomodulatory Strategy as a Treatment against Diseases: History
View Latest Version
Please note this is an old version of this entry, which may differ significantly from the current revision.
Contributor:
Priyanka Bhoj
,
Namdev Togre
,
Vishal Khatri
,
Kalyan Goswami

Lymphatic filariasis is an infection in humans caused by filarial parasites: Wuchereria bancrofti, Brugia malayi, and B. timori. To ensure effective transmission, these parasites evolved with multiple hosts, including a human as a definitive host and the mosquito as an intermediate host. Targeting filarial immunomodulators and manipulating the filariae-driven immune system against the filariae can be a potential therapeutic and prophylactic strategy. 

  • lymphatic filariasis
  • inflammatory diseases
  • filariae

1. Lymphatic Filariasis

In 1997, the World Health Assembly set the goal of eliminating lymphatic filariasis globally by 2020 through mass drug administration (MDA). During MDA, all individuals living in endemic areas received one of these single-dose two-drug combinations: albendazole (ALB) + diethylcarbamazine (DEC) citrate; ALB + ivermectin (IVM) in areas co-endemic for onchocerciasis; or ALB, preferably twice a year, in areas co-endemic for loiasis. However, numerous obstacles stand in the way of successful implementation. These drugs are only effective against microfilariae and not against adult and larval parasites. By the end of 2020, MDA had not yet been delivered to ten endemic countries [1], which raised concerns about the recurrence of filarial infections in countries or areas that were previously declared free of LF infection [2]. One reason for this concern is human migration from endemic to LF-free areas [3][4][5][6]. The majority of migrants were from rural endemic areas, which had poor sanitation, rice fields, and inadequate mosquito control. Moreover, climate change and delays in MDA due to COVID-19 are likely to further sabotage eradication efforts [7][8]. According to the WHO’s 2021 report, 859 million people in 50 countries are at risk of lymphatic filariasis, which requires preventive treatment. As a result, the WHO revised the target date to 2030, using a triple-drug MDA combination of IVM, DEC citrate, and ALB (IDA-MDA), which may result in patient non-compliance [9][10][11][12]. This evidence demands the development of effective vaccines and novel therapeutics.
Strikingly, current antifilarial drugs target the immunomodulatory arsenal of filariae; they alter the host-parasite interface, unmasking the host immune system to access the parasite. The widely used drug DEC is believed to block PGI2 and PGE2 production in both microfilariae and endothelial cells. The resulting vasoconstriction enhances endothelial adhesion and microfilariae immobilization as well as destruction by host platelets and granulocytes [13]. IVM prevents protein release from microfilarial extracellular vesicles by blocking the GluCl channel. These proteins are indispensable for evading the host immune system [14]. Maclean et al. (2021) recently investigated the effects of DEC and IVM treatment on the B. malayi gene expression that may be responsible for filarial clearance from blood circulation [15]. For example, treatment with either IVM or DEC downregulated galectin expression in adults. Galectins, among many other immunomodulatory effects, impede lymphocyte trafficking [16], stimulate alternative macrophage activation [17], and cause T cell apoptosis [18]. Since oxidative and xenobiotic detoxification mediated by antioxidants is a fundamental survival strategy for filariae, researchers synthesized and studied the library of sulphonamide chalcones that affect filarial GSH status, produce oxidative stress, and lead to apoptosis [19][20].
Indeed, drugs can heal existing infections, but they will not prevent infections unless they, or their active metabolites, are removed slowly from the host system, and remain in circulation for a lengthy period. Given that filariae orchestrate the host’s immune system for their own growth and survival, manipulating the host’s defense system against LF could be a viable prophylactic option. Several potential vaccine candidates have been identified and tested for their potential against LF [21]. Many antigens are non-homologous to human and immunomodulatory proteins that subvert the host’s immune response against the parasite.
Table 1 summarizes immune-regulatory proteins that have been evaluated as vaccine candidates. B. malayi immunomodulatory proteins such as heat shock protein 12.6 (BmHsp12.6αc), abundant larval transcript-2 (Bm-ALT-2), and tetraspanin large extracellular loop (Bm-TSP LEL), showed maximum protection in mouse challenge experiments [22][23][24]. To improve the protective efficacy of monovalent vaccines, these best vaccine candidates were fused to prepare a single multivalent vaccine, rBmHAT (BmHsp12.6 + BmALT-2 + BmTSPLEL). Strikingly, it showed >95% protection against B. malayi infection in mice when AL007 or AL019 was used as an adjuvant [25]. However, when administered with alum in non-human primates, rBmHAT provided ~35% protection [26], hinting at a need to change the adjuvant and/or multivalent formulation before using this vaccine in human clinical trials. Adding another immunomodulatory antigen, thioredoxin peroxide (BmTPX-2), to rBmHAT showed >88% protection against the challenge infection [27]. This tetravalent rBmHAXT confers approximately 57% protection against challenge infections in a primate model, which meets the WHO requirement, and hence offers great potential for using this vaccine in human clinical trials [28].
Table 1. Filarial immune-regulatory proteins that have been evaluated as vaccine candidates.
Candidate Vaccine Outcome Reference
Serpin (BmSPN-2) Immune response is strong but short-lived, suggesting that serpins alone are not effective vaccine candidates for long-term immunity [29]
Aabundant larval transcript-2 (BmALT-2) BmALT-2 protein and Bm-alt-2 DNA conferred approximately 75% and 57% protection, respectively [23]
Glutathione-S-transferases (WbGST) 61% protection in Jirds challenge experiments and 65.5% protection in in situ challenge studies [22][30][31]
Small heat shock protein HSP12.6 (BmHsp12.6αc subunit) 83% protection in mouse in situ challenge studies  
Large extracellular loop of tetraspanin (BmTSP-LEL) 64% protection in mouse in situ challenge studies [24]
Bivalent vaccines: HSP12.6 + ALT-2,
HSP12.6 + TSP-LEL,
TSP-LEL + ALT-2		 90%, 80%, and 82% protection in mouse in situ challenge studies, respectively [32]
Trehalose-6-phosphate phosphatase (BmTPP) 78.4% decrease in microfilariae counts and 71% reduction in adult parasite load in Mastomys [33]
Thioredoxin (WbTRX),
Thioredoxin peroxidase (WbTPX)		 57% and 62% protection in Mastomys challenge experiments, respectively [34]
BmHAT Trivalent vaccine Protein and DNA protein prime boost vaccination yielded approximately 95% protection in mice
3 out of 5 vaccinated macaques were protected from challenge infection		 [26][32]
Cystatin-2 in which the amino acid Asn66 was mutated to Lys66 (Bm-CPI-2M) 48.6% and 48.0% at 42 and 90 days post-infection, respectively, with B. malayi L3 filariae [35]
BmALT-2 with Tuftsin as fusion protein 65% larvicidal activity in ADCC experiments [36]
Calreticulin (BmCRT) Offers protection during experimental lymphatic filariasis [37]
BmHAXT Tetravalent vaccine 88% protection in mouse in situ challenge studies
57% protection in rhesus macaques challenge infections
Reduced fecundity and adult worm burden in Jirds		 [27][28][38]
Abbreviations: BmHAT refers to BmHsp12.6 + BmALT-2 + BmTSPLEL; and BmHAXT refers to BmHsp12.6 + BmALT-2 + BmTSPLEL + BmTPX-2.

2. Malaria

Co-infections are common in endemic regions. Control of intracellular pathogens, such as Plasmodium species that cause malaria, Leishmania donovani, Mycobacterium tuberculosis (Mtb), and human immunodeficiency virus (HIV), requires pro-inflammatory Th1 (IL-12, IFN-γ, and TNF-α) and Th17 (IL-17A and IL-23) responses. Increasing evidence suggests that filariae-driven Th2 and Treg immunity can negatively affect the host’s ability to combat these pathogens.
The effect of filarial co-infection on Plasmodium spp. has already been discussed in detail [39]. Human and animal studies on LF/malaria co-infection have provided conflicting results, with some demonstrating more severe malaria in the presence of filarial co-infections and others suggesting filariae-induced protection against malaria, depending on the infection severity and parasite type [40][41][42][43][44][45]. A strong Th1 immune response plays a major role in controlling primary malaria infection. However, the filariae-induced IL-10-dependent Th2 immune response modulates inflammatory IL-12p70/ IFN-γ pathways and increases resistance to malaria [43]. Moreover, pre-existing filarial infection can impair the immunogenicity of anti-Plasmodium vaccination, as evidenced by decreases in plasmodium antigen-specific CD8+ T cells, IFN-γ, and TNF-α production, resulting in reduced cytotoxicity and protection against malarial infection [46]. A simple solution to filarial interference with vaccination efficacy is deworming before vaccination [47]. However, there are several obstacles to drug-induced abolition of filarial infection in endemic locations. These include (1) the lack of an adulticidal or adult-sterilizing drug or vaccine, (2) the time it takes to return to a normal immune response, and (3) the risk of re-infection during the recovery period. Therefore, it is desirable to optimize appropriate vaccination regimes that elicit a multifaceted and potent immune response in filariae-infected individuals [46][47].
Unlike acute malaria, cerebral malaria and malarial sepsis are triggered due to exaggerated pro-inflammatory responses; filariae-derived immunosuppression can protect against this severe immunopathology [40][44]. However, maintaining a filarial infection to avoid an inflammatory exacerbation is not a smart option. In-depth study is required to strike a delicate balance between permissive filarial infection that does not progress to lymphatic filariasis and appropriate immunosuppression that does not lead to severe complications of malaria. Therapies that imitate filariae-derived immunosuppression may be investigated for the treatment of cerebral malaria.

3. Leishmaniasis

Leishmaniasis, the third most common vector-borne disease after malaria and lymphatic filariasis, is caused by the protozoan Leishmania parasite. Visceral leishmaniasis, also known as kala-azar, is caused by L. donovani and L. infantum throughout Asia, North Africa, Latin America, and Southern Europe. Every year, 700,000 to 1 million new cases are reported. The WHO actively encourages research into effective leishmaniasis control [1]. Fractions derived from B. malayi were found to cross-react with sera from hamsters infected with L. donovani, suggesting that these filarial cross-reactive molecules can contribute to the development of anti-leishmanial prophylactics [48]. In vivo studies in hamsters demonstrated that B. malayi L3/adult worms or immunization with a fraction of the adult parasite extract (BmAFII) inhibited the progression of both filarial and L. donovani infections [49][50]. Recently, studies have shown that heat shock protein 60 (BmHSP60) shares several antigenic regions of B- and T-cell epitopes of leishmania counterparts and protects against leishmanial infection via Th1-mediated immune responses and NO production [48][51]. In contrast, a fraction of L. donovani (Ld1) that cross-reacted with sera of B. malayi infected animals facilitated filarial infection. Ld1 consists of eight proteins, including HSPs [52]. Therefore, more comprehensive and in-depth investigations are needed to optimize and develop prophylactics based on cross-reactive rationale in co-endemic regions.
The prevalence of filarial and leishmanial co-infections has been reported in some parts of the world [53]. In the co-infected mouse model, local immune responses to filarial and leishmanial infections were polarized and compartmentalized [54]. These findings contradict acute malarial findings in which microfilariae and Plasmodium share the same niche—blood. In popliteal lymph nodes (which drain the L. major infection site) and thoracic lymph nodes (which drain the L. sigmodontis infection site) immune responses were IFN-γ- and IL-4-dominant, respectively. Moreover, pre-existing helminth infection delayed IFN-γ production and L. major-induced lesion progression [54]. Notably, unlike the leishmanial co-infection model, which confines parasites to the thoracic cavity, the presence of human lymphatic microfilariae in the bloodstream may provide a different immune outcome. Appropriate filarial animal and human population studies are needed to assess whether the immune response to LF/leishmaniasis co-infection is defensive or progressive; such assessment will aid in the development of appropriate and specific immune modulation therapies.

4. Inflammatory Diseases

In developed societies, large-scale deworming programs, reduced exposure to infection due to vaccination, and improved sanitation are associated with an increase in the occurrence of inflammatory and metabolic disorders, supporting the hygiene hypothesis [55][56][57]. The ability of parasitic worms to shift the immune response from Th1 to Th2/Treg has sparked interest in employing live worms as immunotherapy. However, rather than reintroducing an infection, one approach to reducing the incidence of inflammatory and autoimmune disorders is to employ substitutes for these infections that retain their protective benefits.
Many studies regarding the therapeutic potential of helminthic proteins in inflammatory diseases have recently been discussed [58][59]. The use of non-human helminthic proteins may be one reason for unsuccessful clinical trials. Human filariae have co-evolved with the human immune system, suggesting that it is more suitable to use human filarial proteins over other helminthic proteins. There is strong evidence in mouse models that human filarial therapy, excretory-secretory components, and their recombinant molecules can treat and/or prevent inflammatory diseases such as inflammatory bowel disease (IBD), type-1-diabetes (T1D), and rheumatoid arthritis (RA) (Table 2). However, potential filarial proteins have only been tested in the laboratory and have not been tested in clinical trials. Effective coordination can reduce duplication of work, as many proteins have the same mode of action in different inflammatory diseases. For example, rBmALT-2 has been found to reduce the severity of T1D and IBD by downregulating IFN-γ and upregulating IL-10 and IgG1/IgG2a [60][61]. Although promising results have been achieved with human lymphatic filarial therapy, many questions, such as those regarding optimal dose, treatment duration, immunization route, safety profile, and cellular mode of action, remain unanswered. There is considerable scope for research in this area. For instance, site-directed administration of filarial immunomodulatory proteins using anti-colitic probiotics can provide effective IBD prevention/cure therapy [62]. A series of research studies, ranging from basic to clinical, is essential to evaluate the efficacy, safety, tolerability, and ethical implications of genetically modified immunobiotics.
Table 2. Human lymphatic filariae-derived molecules as a therapy against inflammatory diseases.
Lymphatic Filarial Protein Experimental Disease Model Study Outcome Mechanism of Action Reference
Recombinant B. malayi Cystatin (rBmCys) DSS-induced acute colitis Down-regulated inflammatory responses and alleviated symptoms and pathology of colitis. Elevated IL-10 + FoxP3 + Tregs, IgM + B1a cells and AAMs in the colon and peritoneal cavity.
Reduced expression of Th1 and Th17 cytokines in serum and spleen.		 [63][64]
rBmCys mBSA-induced rheumatoid arthritis (RA) Both preventive and therapeutic effects on RA.
Decreased synovitis, bone erosion, fibrosis, and influx of inflammatory cells in hind paw joints.		 Shift from Th1 to IL-4 and IL-10 secreting Th2 immune response. [65][66]
Peptide fragments of rBmCys DSS-induced acute colitis Anti-inflammatory effect on DSS-induced colitis in mice.
Reversed the gross and histopathological changes in the colitic colon.		 Decreased F4/80 + TLR-4 + CD11c+ macrophages in peritoneum.
Reduced LY6G+ cells and MPO+ cells and increased FoxP3 + Tregs in colon.		 [67]
Recombinant B. malayi abundant larval transcript-2 (rBmALT-2) DSS-induced acute colitis More effective in preventive mode compared to therapeutic treatment against colitis. Associated with downregulation of IFN-γ, IL-6, IL-17, and upregulation of IL-10 cytokines in spleen. [60]
Recombinant W. bancrofti L-2 (rWbL2) DSS-induced acute colitis Reduced lymphocyte infiltration and decreased epithelial damage in colons of treated mice. Shift towards Th2 response as reflected by increased IL-10, and decreased IFN-γ and TNF-α by splenocytes.
IgG1/IgG2 ratio in the sera.		 [68]
rBmALT-2, rBmCys, and rWbL-2 individually and in combinations DSS-induced chronic colitis All treatment strategies improved the clinicopathologic status of chronic colitis.
rBmALT-2 + rBmCys showed the most prominent therapeutic effect.		 Downregulated IFN-γ and TNF-α expression, upregulated IL-10, and TGF-β expression in the splenocytes.
Reduction in activated NF-κB level in the colon.
Increased IgG1/IgG2 ratio in the sera.		 [69]
rWbL-2, rBmALT-2, and rWbL-2 + rBmALT-2 STZ-induced T1D Led to reduced lymphocytic infiltration, islet damage, and blood glucose levels. Decreased TNF-α and IFN-γ, and increased Il-4, IL-5, and IL-10 production in splenocytes.
Elevated insulin-specific IgG1 and antigen-specific IgE antibodies in the sera.		 [61]
B. malayi adult soluble (Bm A S) and microfilarial excretory-secretory proteins (Bm Mf ES) STZ-induced T1D More effective when used as curative rather than a preventive treatment.
Reduced inflammatory changes in pancreatic islet cell architecture and fasting blood glucose levels.		 Decreased TNF-α and IFN-γ, and increased IL-10 production in the splenocytes.
Elevated anti-insulin IgG1 antibodies indicating a skewed response towards Th2 type in the sera.		 [70]
B. malayi asparaginyl-tRNA synthetase (BmAsnRS) T-cell transfer colitis Resolves intestinal inflammation. Increase in CD8+ T cells in the lamina propria compartment, with a corresponding increase in CD4+ cells in spleens of treated mice.
Decrease in IFN-γ and IL-17, and increase in IL-4 and IL-10 in spleens, mesenteric lymph nodes, and lamina propria of treated mice.
Induced upregulation of IL-10 and IL-22 receptors.		 [71]
Brugia malayi K1 (BmK1) - Inhibits the delayed-type hypersensitivity response. Blocked Kv1.3 receptors in human T cells.
Suppressed the proliferation of rat CCR7-effector memory T cells and production of IFN-γ.		 [72]

This entry is adapted from the peer-reviewed paper 10.3390/vaccines10081235

References

  1. World Health Organization Lymphatic Filariasis. 2022. Lymphatic Filariasis. Available online: https://www.who.int/news-room/fact-sheets/detail/lymphatic-filariasis (accessed on 2 June 2022).
  2. Mallawarachchi, C.H.; Nilmini Chandrasena, T.G.A.; Premaratna, R.; Mallawarachchi, S.M.N.S.M.; de Silva, N.R. Human Infection with Sub-Periodic Brugia spp. in Gampaha District, Sri Lanka: A Threat to Filariasis Elimination Status? Parasites Vectors 2018, 11, 68.
  3. George, S.; Joy, T.M.; Kumar, A.; Panicker, K.N.; George, L.S.; Raj, M.; Leelamoni, K.; Nair, P. Prevalence of Neglected Tropical Diseases (Leishmaniasis and Lymphatic Filariasis) and Malaria among a Migrant Labour Settlement in Kerala, India. J. Immigr. Minority Health 2019, 21, 563–569.
  4. Zuchi, A.; Prust, L.T.; Rocha, A.; Araújo, J.; da Silva, P.S.; Fiorillo, K.; Brandão, E.; Ximenes, C.; Lopes, F.; Ponzi, C.C. Screening and Evaluation of Lymphatic Filariasis in Immigrants from Endemic Countries Residing in a Focus Where It Is Considered Eliminated in the Southern Region of Brazil: A Risk of Reemergence? Acta Trop. 2017, 176, 192–196.
  5. Da Silva, E.F.; de Lacerda, M.V.G.; Fontes, G.; Mourão, M.P.G.; Martins, M. Wuchereria bancrofti Infection in Haitian Immigrants and the Risk of Re-Emergence of Lymphatic Filariasis in the Brazilian Amazon. Rev. Soc. Bras. Med. Trop. 2017, 50, 256–259.
  6. Xu, Z.; Lau, C.L.; Zhou, X.; Fuimaono, S.; Soares Magalhães, R.J.; Graves, P.M. The Extensive Networks of Frequent Population Mobility in the Samoan Islands and Their Implications for Infectious Disease Transmission. Sci. Rep. 2018, 8, 10136.
  7. Prada, J.M.; Stolk, W.A.; Davis, E.L.; Touloupou, P.; Sharma, S.; Muñoz, J.; Caja Rivera, R.M.; Reimer, L.J.; Michael, E.; de Vlas, S.J.; et al. Delays in Lymphatic Filariasis Elimination Programmes Due to COVID-19, and Possible Mitigation Strategies. Trans. R. Soc. Trop. Med. Hyg. 2021, 115, 261–268.
  8. Bizhani, N.; Hashemi Hafshejani, S.; Mohammadi, N.; Rezaei, M.; Rokni, M.B. Lymphatic Filariasis in Asia: A Systematic Review and Meta-Analysis. Parasitol. Res. 2021, 120, 411–422.
  9. Hussain, M.A.; Sitha, A.K.; Swain, S.; Kadam, S.; Pati, S. Mass Drug Administration for Lymphatic Filariasis Elimination in a Coastal State of India: A Study on Barriers to Coverage and Compliance. Infect. Dis. Poverty 2014, 3, 31.
  10. Ahorlu, C.S.K.; Koka, E.; Adu-Amankwah, S.; Otchere, J.; de Souza, D.K. Community Perspectives on Persistent Transmission of Lymphatic Filariasis in Three Hotspot Districts in Ghana after 15 Rounds of Mass Drug Administration: A Qualitative Assessment. BMC Public Health 2018, 18, 238.
  11. Willis, G.A.; Mayfield, H.J.; Kearns, T.; Naseri, T.; Thomsen, R.; Gass, K.; Sheridan, S.; Graves, P.M.; Lau, C.L. A Community Survey of Coverage and Adverse Events Following Country-Wide Triple-Drug Mass Drug Administration for Lymphatic Filariasis Elimination, Samoa 2018. PLOS Negl. Trop. Dis. 2020, 14, e0008854.
  12. de Souza, D.K.; Gass, K.; Otchere, J.; Htet, Y.M.; Asiedu, O.; Marfo, B.; Biritwum, N.-K.; Boakye, D.A.; Ahorlu, C.S. Review of MDA Registers for Lymphatic Filariasis: Findings, and Potential Uses in Addressing the Endgame Elimination Challenges. PLoS Negl. Trop. Dis. 2020, 14, e0008306.
  13. Martin, R.J. Modes of Action of Anthelmintic Drugs. Vet. J. 1997, 154, 11–34.
  14. Moreno, Y.; Nabhan, J.F.; Solomon, J.; Mackenzie, C.D.; Geary, T.G. Ivermectin Disrupts the Function of the Excretory-Secretory Apparatus in Microfilariae of Brugia malayi. Proc. Natl. Acad. Sci. USA 2010, 107, 20120–20125.
  15. Maclean, M.J.; Lorenz, W.W.; Dzimianski, M.T.; Anna, C.; Moorhead, A.R.; Reaves, B.J.; Wolstenholme, A.J. Effects of Diethylcarbamazine and Ivermectin Treatment on Brugia malayi Gene Expression in Infected Gerbils (Meriones unguiculatus). Parasitol. Open 2019, 5, e2.
  16. Norling, L.V.; Sampaio, A.L.F.; Cooper, D.; Perretti, M. Inhibitory Control of Endothelial Galectin-1 on in Vitro and in Vivo Lymphocyte Trafficking. FASEB J. 2008, 22, 682–690.
  17. MacKinnon, A.C.; Farnworth, S.L.; Hodkinson, P.S.; Henderson, N.C.; Atkinson, K.M.; Leffler, H.; Nilsson, U.J.; Haslett, C.; Forbes, S.J.; Sethi, T. Regulation of Alternative Macrophage Activation by Galectin-3. J. Immunol. 2008, 180, 2650–2658.
  18. Wang, W.; Wang, S.; Zhang, H.; Yuan, C.; Yan, R.; Song, X.; Xu, L.; Li, X. Galectin Hco-Gal-m from Haemonchus Contortus Modulates Goat Monocytes and T Cell Function in Different Patterns. Parasites Vectors 2014, 7, 342.
  19. Bahekar, S.P.; Hande, S.V.; Agrawal, N.R.; Chandak, H.S.; Bhoj, P.S.; Goswami, K.; Reddy, M.V.R. Sulfonamide Chalcones: Synthesis and in Vitro Exploration for Therapeutic Potential against Brugia malayi. Eur. J. Med. Chem. 2016, 124, 262–269.
  20. Bhoj, P.S.; Bahekar, S.; Khatri, V.; Singh, N.; Togre, N.S.; Goswami, K.; Chandak, H.S.; Dash, D. Role of Glutathione in Chalcone Derivative Induced Apoptosis of Brugia malayi and Its Possible Therapeutic Implication. Acta Parasitol. 2021, 66, 406–415.
  21. Kalyanasundaram, R.; Khatri, V.; Chauhan, N. Advances in Vaccine Development for Human Lymphatic Filariasis. Trends Parasitol. 2020, 36, 195–205.
  22. Dakshinamoorthy, G.; Samykutty, A.K.; Munirathinam, G.; Shinde, G.B.; Nutman, T.; Reddy, M.V.; Kalyanasundaram, R. Biochemical Characterization and Evaluation of a Brugia malayi Small Heat Shock Protein as a Vaccine against Lymphatic Filariasis. PLoS ONE 2012, 7, e34077.
  23. Thirugnanam, S.; Pandiaraja, P.; Ramaswamy, K.; Murugan, V.; Gnanasekar, M.; Nandakumar, K.; Reddy, M.V.R.; Kaliraj, P. Brugia malayi: Comparison of Protective Immune Responses Induced by Bm-Alt-2 DNA, Recombinant Bm-ALT-2 Protein and Prime-Boost Vaccine Regimens in a Jird Model. Exp. Parasitol. 2007, 116, 483–491.
  24. Dakshinamoorthy, G.; Munirathinam, G.; Stoicescu, K.; Reddy, M.V.; Kalyanasundaram, R. Large Extracellular Loop of Tetraspanin as a Potential Vaccine Candidate for Filariasis. PLoS ONE 2013, 8, e77394.
  25. 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.
  26. Dakshinamoorthy, G.; von Gegerfelt, A.; Andersen, H.; Lewis, M.; Kalyanasundaram, R. Evaluation of a Multivalent Vaccine against Lymphatic Filariasis in Rhesus Macaque Model. PLoS ONE 2014, 9, e112982.
  27. Chauhan, N.; Khatri, V.; Banerjee, P.; Kalyanasundaram, R. Evaluating the Vaccine Potential of a Tetravalent Fusion Protein (RBmHAXT) Vaccine Antigen Against Lymphatic Filariasis in a Mouse Model. Front. Immunol. 2018, 9, 01520.
  28. Khatri, V.; Chauhan, N.; Vishnoi, K.; von Gegerfelt, A.; Gittens, C.; Kalyanasundaram, R. Prospects of Developing a Prophylactic Vaccine against Human Lymphatic Filariasis—Evaluation of Protection in Non-Human Primates. Int. J. Parasitol. 2018, 48, 773–783.
  29. Zang, X.; Atmadja, A.K.; Gray, P.; Allen, J.E.; Gray, C.A.; Lawrence, R.A.; Yazdanbakhsh, M.; Maizels, R.M. The Serpin Secreted by Brugia malayi Microfilariae, Bm-SPN-2, Elicits Strong, but Short-Lived, Immune Responses in Mice and Humans. J. Immunol. 2000, 165, 5161–5169.
  30. Veerapathran, A.; Dakshinamoorthy, G.; Gnanasekar, M.; Reddy, M.V.R.; Kalyanasundaram, R. Evaluation of Wuchereria bancrofti GST as a Vaccine Candidate for Lymphatic Filariasis. PLoS Negl. Trop. Dis. 2009, 3, e457.
  31. Andure, D.; Pote, K.; Khatri, V.; Amdare, N.; Padalkar, R.; Reddy, M.V.R. Immunization with Wuchereria bancrofti Glutathione-S-Transferase Elicits a Mixed Th1/Th2 Type of Protective Immune Response Against Filarial Infection in Mastomys. Indian J. Clin. Biochem. 2016, 31, 423–430.
  32. Dakshinamoorthy, G.; Samykutty, A.K.; Munirathinam, G.; Reddy, M.V.; Kalyanasundaram, R. Multivalent Fusion Protein Vaccine for Lymphatic Filariasis. Vaccine 2013, 31, 1616–1622.
  33. Kushwaha, S.; Singh, P.K.; Rana, A.K.; Misra-Bhattacharya, S. Immunization of Mastomys Coucha with Brugia malayi Recombinant Trehalose-6-Phosphate Phosphatase Results in Significant Protection against Homologous Challenge Infection. PLoS ONE 2013, 8, e72585.
  34. Prince, P.R.; Madhumathi, J.; Anugraha, G.; Jeyaprita, P.J.; Reddy, M.V.R.; Kaliraj, P. Tandem Antioxidant Enzymes Confer Synergistic Protective Responses in Experimental Filariasis. J. Helminthol. 2014, 88, 402–410.
  35. Arumugam, S.; Wei, J.; Ward, D.; Abraham, D.; Lustigman, S.; Zhan, B.; Klei, T.R. Vaccination with a Genetically Modified Brugia malayi Cysteine Protease Inhibitor-2 Reduces Adult Parasite Numbers and Affects the Fertility of Female Worms Following a Subcutaneous Challenge of Mongolian Gerbils (Meriones unguiculatus) with B. malayi Infective Larvae. Int. J. Parasitol. 2014, 44, 675–679.
  36. Paul, R.; Ilamaran, M.; Khatri, V.; Amdare, N.; Reddy, M.V.R.; Kaliraj, P. Immunological Evaluation of Fusion Protein of Brugia malayi Abundant Larval Protein Transcript-2 (BmALT-2) and Tuftsin in Experimental Mice Model. Parasite Epidemiol. Control 2019, 4, e00092.
  37. Yadav, S.; Sharma, P.; Sharma, A.; Ganga, L.; Saxena, J.K.; Srivastava, M. Immunization with Brugia malayi Calreticulin Protein Generates Robust Antiparasitic Immunity and Offers Protection during Experimental Lymphatic Filariasis. ACS Infect. Dis. 2021, 7, 790–799.
  38. Khatri, V.; Chauhan, N.; Kalyanasundaram, R. Fecundity of Adult Female Worms Were Affected When Brugia malayi Infected Mongolian Gerbils Were Immunized with a Multivalent Vaccine (RBmHAXT) against Human Lymphatic Filarial Parasite. Acta Trop. 2020, 208, 105487.
  39. Metenou, S.; Babu, S.; Nutman, T.B. Impact of Filarial Infections on Coincident Intracellular Pathogens. Curr. Opin. HIV AIDS 2012, 7, 231–238.
  40. Yan, Y.; Inuo, G.; Akao, N.; Tsukidate, S.; Fujita, K. Down-Regulation of Murine Susceptibility to Cerebral Malaria by Inoculation with Third-Stage Larvae of the Filarial Nematode Brugia pahangi. Parasitology 1997, 114, 333–338.
  41. Graham, A.L.; Lamb, T.J.; Read, A.F.; Allen, J.E. Malaria-Filaria Coinfection in Mice Makes Malarial Disease More Severe Unless Filarial Infection Achieves Patency. J. Infect. Dis. 2005, 191, 410–421.
  42. Fernández Ruiz, D.; Dubben, B.; Saeftel, M.; Endl, E.; Deininger, S.; Hoerauf, A.; Specht, S. Filarial Infection Induces Protection against P. berghei Liver Stages in Mice. Microbes Infect. 2009, 11, 172–180.
  43. Metenou, S.; Dembélé, B.; Konate, S.; Dolo, H.; Coulibaly, S.Y.; Coulibaly, Y.I.; Diallo, A.A.; Soumaoro, L.; Coulibaly, M.E.; Sanogo, D.; et al. Patent Filarial Infection Modulates Malaria-Specific Type 1 Cytokine Responses in an IL-10-Dependent Manner in a Filaria/Malaria-Coinfected Population. J. Immunol. 2009, 183, 916–924.
  44. Specht, S.; Ruiz, D.F.; Dubben, B.; Deininger, S.; Hoerauf, A. Filaria-Induced IL-10 Suppresses Murine Cerebral Malaria. Microbes Infect. 2010, 12, 635–642.
  45. Panda, M.; Sahoo, P.K.; das Mohapatra, A.; kanti Dutta, S.; Thatoi, P.K.; Tripathy, R.; Das, B.K.; Satpathy, A.K.; Ravindran, B. Decreased Prevalence of Sepsis but Not Mild or Severe P. falciparum Malaria Is Associated with Pre-Existing Filarial Infection. Parasit Vectors 2013, 6, 203.
  46. Kolbaum, J.; Tartz, S.; Hartmann, W.; Helm, S.; Nagel, A.; Heussler, V.; Sebo, P.; Fleischer, B.; Jacobs, T.; Breloer, M. Nematode-Induced Interference with the Anti-Plasmodium CD8+ T-Cell Response Can Be Overcome by Optimizing Antigen Administration. Eur. J. Immunol. 2012, 42, 890–900.
  47. Noland, G.S.; Chowdhury, D.R.; Urban, J.F.; Zavala, F.; Kumar, N. Helminth Infection Impairs the Immunogenicity of a Plasmodium Falciparum DNA Vaccine, but Not Irradiated Sporozoites, in Mice. Vaccine 2010, 28, 2917–2923.
  48. Verma, R.; Joseph, S.K.; Kushwaha, V.; Kumar, V.; Siddiqi, M.I.; Vishwakarma, P.; Shivahare, R.; Gupta, S.; Murthy, P.K. Cross Reactive Molecules of Human Lymphatic Filaria Brugia malayi Inhibit Leishmania Donovani Infection in Hamsters. Acta Trop. 2015, 152, 103–111.
  49. Murthy, P.K.; Dixit, S.; Gaur, R.L.; Kumar, R.; Sahoo, M.K.; Shakya, N.; Joseph, S.K.; Palne, S.; Gupta, S. Influence of Brugia malayi Life Stages and BmAFII Fraction on Experimental Leishmania Donovani Infection in Hamsters. Acta Trop. 2008, 106, 81–89.
  50. Sahoo, M.K.; Sisodia, B.S.; Dixit, S.; Joseph, S.K.; Gaur, R.L.; Verma, S.K.; Verma, A.K.; Shasany, A.K.; Dowle, A.A.; Murthy, P.K. Immunization with Inflammatory Proteome of Brugia malayi Adult Worm Induces a Th1/Th2-Immune Response and Confers Protection against the Filarial Infection. Vaccine 2009, 27, 4263–4271.
  51. Kushwaha, V.; Kaur, S. Cross-Protective Efficacy of Immuno-Stimulatory Recombinant Brugia malayi Protein HSP60 against the Leishmania Donovani in BALB/c Mice. Biologicals 2021, 72, 18–26.
  52. Verma, R.; Kushwaha, V.; Pandey, S.; Thota, J.R.; Vishwakarma, P.; Parmar, N.; Yadav, P.K.; Tewari, P.; Kar, S.; Shukla, P.K.; et al. Leishmania Donovani Molecules Recognized by Sera of Filaria Infected Host Facilitate Filarial Infection. Parasitol. Res. 2018, 117, 2901–2912.
  53. Sangare, M.B.; Coulibaly, Y.I.; Coulibaly, S.Y.; Coulibaly, M.E.; Traore, B.; Dicko, I.; Sissoko, I.M.; Samake, S.; Traore, S.F.; Nutman, T.B.; et al. A Cross-Sectional Study of the Filarial and Leishmania Co-Endemicity in Two Ecologically Distinct Settings in Mali. Parasit Vectors 2018, 11, 18.
  54. Lamb, T.J.; Graham, A.L.; le Goff, L.; Allen, J.E. Co-Infected C57BL/6 Mice Mount Appropriately Polarized and Compartmentalized Cytokine Responses to Litomosoides Sigmodontis and Leishmania Major but Disease Progression Is Altered. Parasite Immunol. 2005, 27, 317–324.
  55. Rook, G.A.W. The Hygiene Hypothesis and the Increasing Prevalence of Chronic Inflammatory Disorders. Trans. R. Soc. Trop. Med. Hyg. 2007, 101, 1072–1074.
  56. Caraballo, L. The Tropics, Helminth Infections and Hygiene Hypotheses. Expert Rev. Clin. Immunol. 2018, 14, 99–102.
  57. Bach, J.-F. Revisiting the Hygiene Hypothesis in the Context of Autoimmunity. Front. Immunol. 2021, 11, 615192.
  58. Smallwood, T.B.; Giacomin, P.R.; Loukas, A.; Mulvenna, J.P.; Clark, R.J.; Miles, J.J. Helminth Immunomodulation in Autoimmune Disease. Front. Immunol. 2017, 8, 00453.
  59. Shi, W.; Xu, N.; Wang, X.; Vallée, I.; Liu, M.; Liu, X. Helminth Therapy for Immune-Mediated Inflammatory Diseases: Current and Future Perspectives. J. Inflamm. Res. 2022, 15, 475–491.
  60. Khatri, V.; Amdare, N.; Yadav, R.S.; Tarnekar, A.; Goswami, K.; Reddy, M.V.R. Brugia malayi Abundant Larval Transcript 2 Protein Treatment Attenuates Experimentally-Induced Colitis in Mice. Indian J. Exp. Biol. 2015, 53, 732–739.
  61. Amdare, N.P.; Khatri, V.K.; Yadav, R.S.P.; Tarnekar, A.; Goswami, K.; Reddy, M.V.R. Therapeutic Potential of the Immunomodulatory Proteins Wuchereria bancrofti L2 and Brugia malayi Abundant Larval Transcript 2 against Streptozotocin-Induced Type 1 Diabetes in Mice. J. Helminthol. 2017, 91, 539–548.
  62. Ou, B.; Yang, Y.; Tham, W.L.; Chen, L.; Guo, J.; Zhu, G. Genetic Engineering of Probiotic Escherichia Coli Nissle 1917 for Clinical Application. Appl. Microbiol. Biotechnol. 2016, 100, 8693–8699.
  63. Khatri, V.; Amdare, N.; Tarnekar, A.; Goswami, K.; Reddy, M.V.R. Brugia malayi Cystatin Therapeutically Ameliorates Dextran Sulfate Sodium-Induced Colitis in Mice. J. Dig. Dis. 2015, 16, 585–594.
  64. Bisht, N.; Khatri, V.; Chauhan, N.; Kalyanasundaram, R. Cystatin from Filarial Parasites Suppress the Clinical Symptoms and Pathology of Experimentally Induced Colitis in Mice by Inducing T-Regulatory Cells, B1-Cells, and Alternatively Activated Macrophages. Biomedicines 2019, 7, 85.
  65. Yadav, R.S.P.; Khatri, V.; Amdare, N.; Goswami, K.; Shivkumar, V.B.; Gangane, N.; Reddy, M.V.R. Immuno-Modulatory Effect and Therapeutic Potential of Brugia malayi Cystatin in Experimentally Induced Arthritis. Indian J. Clin. Biochem. 2016, 31, 203–208.
  66. Yadav RS, P.; Khatri, V.; Amdare, N.; Goswami, K.; Shivkumar, V.B.; Gangane, N.; Reddy, M.V.R. Evaluation of Preventive Effect of Brugia malayi Recombinant Cystatin on MBSA-Induced Experimental Arthritis. Indian J. Exp. Biol. 2017, 55, 655–660.
  67. Khatri, V.; Chauhan, N.; Prasanna Kumar, S.B.; Kalyanasundaram, R. Peptide Fragments of Cystatin Protein from Filarial Parasite Has Potent Anti-Inflammatory Effect on DSS-Induced Colitis in Mouse. J. Immunol. 2020, 204, 237.28.
  68. Togre, N.; Bhoj, P.; Amdare, N.; Goswami, K.; Tarnekar, A.; Shende, M. Immunomodulatory Potential of Recombinant Filarial Protein, RWbL2, and Its Therapeutic Implication in Experimental Ulcerative Colitis in Mouse. Immunopharmacol. Immunotoxicol. 2018, 40, 483–490.
  69. Togre, N.; Bhoj, P.; Goswami, K.; Tarnekar, A.; Patil, M.; Shende, M. Human Filarial Proteins Attenuate Chronic Colitis in an Experimental Mouse Model. Parasite Immunol. 2018, 40, e12511.
  70. Amdare, N.; Khatri, V.; Yadav, R.S.P.; Tarnekar, A.; Goswami, K.; Reddy, M.V.R. Brugia malayi Soluble and Excretory-Secretory Proteins Attenuate Development of Streptozotocin-Induced Type 1 Diabetes in Mice. Parasite Immunol. 2015, 37, 624–634.
  71. Kron, M.A.; Metwali, A.; Vodanovic-Jankovic, S.; Elliott, D. Nematode Asparaginyl-TRNA Synthetase Resolves Intestinal Inflammation in Mice with T-Cell Transfer Colitis. Clin. Vaccine Immunol. 2013, 20, 276–281.
  72. Chhabra, S.; Chang, S.C.; Nguyen, H.M.; Huq, R.; Tanner, M.R.; Londono, L.M.; Estrada, R.; Dhawan, V.; Chauhan, S.; Upadhyay, S.K.; et al. Kv1.3 Channel-blocking Immunomodulatory Peptides from Parasitic Worms: Implications for Autoimmune Diseases. FASEB J. 2014, 28, 3952–3964.
More
© Text is available under the terms and conditions of the Creative Commons Attribution (CC BY) license; additional terms may apply. By using this site, you agree to the Terms and Conditions and Privacy Policy.
This entry is offline, you can click here to edit this entry!
Feedback