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Defensins Potentiate a Neutralizing Antibody Response to Enteric Viral Infection.

ABSTRACT: ?-defensins are abundant antimicrobial peptides with broad, potent antibacterial, antifungal, and antiviral activities in vitro. Although their contribution to host defense against bacteria in vivo has been demonstrated, comparable studies of their antiviral activity in vivo are lacking. Using a mouse model deficient in activated ?-defensins in the small intestine, we show that Paneth cell ?-defensins protect mice from oral infection by a pathogenic virus, mouse adenovirus 1 (MAdV-1). Survival differences between mouse genotypes are lost upon parenteral MAdV-1 infection, strongly implicating a role for intestinal defenses in attenuating pathogenesis. Although differences in ?-defensin expression impact the composition of the ileal commensal bacterial population, depletion studies using broad-spectrum antibiotics revealed no effect of the microbiota on ?-defensin-dependent viral pathogenesis. Moreover, despite the sensitivity of MAdV-1 infection to ?-defensin neutralization in cell culture, we observed no barrier effect due to Paneth cell ?-defensin activation on the kinetics and magnitude of MAdV-1 dissemination to the brain. Rather, a protective neutralizing antibody response was delayed in the absence of ?-defensins. This effect was specific to oral viral infection, because antibody responses to parenteral or mucosal ovalbumin exposure were not affected by ?-defensin deficiency. Thus, ?-defensins play an important role as adjuvants in antiviral immunity in vivo that is distinct from their direct antiviral activity observed in cell culture.

SUBMITTER: Gounder AP

PROVIDER: S-EPMC4774934 | biostudies-literature | 2016 Mar

REPOSITORIES: biostudies-literature

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Project description:BackgroundThe spread of the vaccine-resistant Omicron severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants threatens unvaccinated and fully vaccinated individuals, and accelerated booster vaccination campaigns are underway to mitigate the ongoing wave of Omicron cases. The immunity provided by standard vaccine regimens, boosted regimens, and immune responses elicited by vaccination plus natural infection remain incompletely understood. The magnitude, quality, and durability of serological responses, and the likelihood of protection against future SARS-CoV-2 variants following these modes of exposure, are poorly characterized but are critical to the future trajectory of the coronavirus disease 2019 (COVID-19) pandemic.MethodsNinety-nine individuals were semi-randomly selected from a larger vaccination cohort following vaccination and, in some cases, breakthrough infection. We analyzed spike receptor-binding domain-specific immunoglobulin G (IgG), IgA, and IgM by enzyme-linked immunosorbent assay, neutralizing antibody titers against live SARS-CoV-2 variants, and antibody-dependent cell-mediated phagocytosis.FindingsIn 99 vaccinated adults, compared with responses after two doses of an mRNA regimen, the immune responses 3 months after a third vaccine dose and 1 month after breakthrough infection due to prior variants show dramatic increases in magnitude, potency, and breadth, including increased antibody-dependent cellular phagocytosis and robust neutralization of the currently circulating Omicron BA.2 variant.ConclusionsBoosters and natural infection substantially boost immune responses. As the number of Omicron sub-variant cases rise and as global vaccination and booster campaigns continue, an increasing proportion of the world's population will acquire potent immune responses that may be protective against future SARS-CoV-2 variants.FundingThis work was funded by the M. J. Murdock Charitable Trust, the OHSU Foundation, the NIH (T32HL083808), and OHSU Innovative IDEA.

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Defensins Potentiate a Neutralizing Antibody Response to Enteric Viral Infection.

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