Studying the Immunotherapeutic Potential of Chicken Interleukin-17A (ChIL-17A) against Influenza Type A Virus (IAV) Infections

Bhowmick, Sucharita (2025) Studying the Immunotherapeutic Potential of Chicken Interleukin-17A (ChIL-17A) against Influenza Type A Virus (IAV) Infections. PhD thesis, Indian Institute of Science Education and Research Kolkata.

Text (PhD thesis of Sucharita Bhowmick (19RS097)) 19RS097.pdf - Submitted Version Restricted to Repository staff only Download (8MB)

Abstract

Low pathogenic avian influenza virus (LPAIV) remains the most common subtype of type A influenza virus that causes moderate to severe infection in poultry with significant zoonotic and pandemic potential. Although LPAIV causes subclinical infections, it often causes respiratory signs like coughing, sneezing, and ocular and nasal exudes, as well as decreased egg production in domestic birds. Moreover, LPAIVs can potentially emerge into highly pathogenic forms, affecting avian and human populations. However, the conventional means to prevent intra- or inter-species dissemination of avian influenza virus (AIV) is highly challenging due to high mutability, increasing drug resistance, and limited vaccine availability. The recent advancement in understanding the host factors in orchestrating qualitatively different immune responses against influenza Type A virus (IAV) has changed the perception of the conventional approaches for controlling AIV infection in chickens. Therefore, an alternate method of preventing AIV infections, cytokine-based approaches to augment antiviral host defense, has gained significant attention. In addition to performing an essential role in viral clearance, cytokines also engage in tissue repair and maintain homeostasis of the immune system. However, the selective application of cytokines is critical since unregulated expression of cytokines, particularly pro-inflammatory ones, can cause substantial tissue damage during acute phases of immune responses. In contrast to the function of other inflammatory cytokines, interleukin-17A (IL-17A) has been known as a ‘double-edged sword,’ indicating that alongside its ability to induce antiviral host responses, IL-17A can promote certain viral infections. Moreover, based on cytokine types and their impact on the intestinal microbiota, outcomes of cytokine-gut microflora interaction can have a critical effect on overall host defense against AIV infections. To this end, in the current study, first, we studied the effect of exogenous administration of chicken IL-17A (ChIL-17A) in regulating anti-viral host responses against IAV infection in chickens. For this, we bioengineered a food-grade Lactic Acid Producing Bacteria (LAB), Lactococcus lactis (L. lactis), to express and secret bioactive recombinant chicken IL-17A (sChIL-17A) protein. The functionality of sChIL-17A was confirmed by transcriptional upregulation of several downstream effector molecules primarily associated with the IL-17A signaling pathways. Consistent with our hypothesis, we observed that sChIL-17A pre-treatment could significantly increase the expression of major proinflammatory cytokines [(GM-CSF) (CSF3 in the chicken), IL-6, and both type I and type II interferons] to restrict and limit the viral replication, ensuring effective in vitro protection against heterosubtypic IAVs infections such as A/turkey/Wisconsin/1/1966(H9N2) and A/PR/8/1934(H1N1) viruses. Considering the role of gut health in fostering innate or local host immune responses, we further studied the contributory relationships between gut microbiota and host immune responses against influenza virus infection in chickens. In the present study delineates that mucosal delivery of rL. lactis expressing ChIL-17A alongside triggering pro-inflammatory responses can drive a positive shift in beneficial gut microbiota such as phylum Firmicutes in contrast to a modest decrease in phylum Actinobacteriota and Proteobacteria, known for negative gut floral indicators. Together, the data presented in this work suggest that exogenous application of sChIL-17A secreted by a recombinant bioengineered LAB vector may represent an alternative strategy for improving antiviral host defense against influenza A virus infection in chickens. Moreover, we propose that ChIL-17A-mediated selective expansion of beneficial gut microbiota could form a healthy microbial community to augment effective immune protection against IAV infections in chickens.

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