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Interleukin-36? provides protection against HSV-1 infection, but does not modulate initiation of adaptive immune responses.

ABSTRACT: Interleukin-36 (IL-36) represents three cytokines, IL-36?, IL-36? and IL-36?, which bind to the same receptor, IL-1RL2; however, their physiological function(s) remain poorly understood. Here, the role of IL-36 in immunity against HSV-1 was examined using the flank skin infection mouse model. Expression analyses revealed increased levels of IL-36? and IL-36? mRNA in infected skin, while constitutive IL-36? levels remained largely unchanged. In human keratinocytes, IL-36? mRNA was induced by HSV-1, while IL-1? and TNF? increased all three IL-36 mRNAs. The dominant alternative splice variant of human IL-36? mRNA was isoform 2, which is the ortholog of the known mouse IL-36? mRNA. Mice deficient in IL-36?, but not IL-36? or IL-36?, succumbed more frequently to HSV-1 infection than wild type mice. Furthermore, IL-36?-/- mice developed larger zosteriform skin lesions along infected neurons. Levels of HSV-1 specific antibodies, CD8+ cells and IFN?-producing CD4+ cells were statistically equal in wild type and IL-36?-/- mice, suggesting similar initiation of adaptive immunity in the two strains. This correlated with the time at which HSV-1 genome and mRNA levels in primary skin lesions started to decline in both wild type and IL-36?-/- mice. Our data indicate that IL-36? has previously unrecognized functions protective against HSV-1 infection.

SUBMITTER: Milora KA

PROVIDER: S-EPMC5517484 | biostudies-literature | 2017 Jul

REPOSITORIES: biostudies-literature

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Interleukin-36β provides protection against HSV-1 infection, but does not modulate initiation of adaptive immune responses.

Milora Katelynn A KA Uppalapati Siva R SR Sanmiguel Julio C JC Zou Wei W Jensen Liselotte E LE

Scientific reports 20170719 1

Interleukin-36 (IL-36) represents three cytokines, IL-36α, IL-36β and IL-36γ, which bind to the same receptor, IL-1RL2; however, their physiological function(s) remain poorly understood. Here, the role of IL-36 in immunity against HSV-1 was examined using the flank skin infection mouse model. Expression analyses revealed increased levels of IL-36α and IL-36β mRNA in infected skin, while constitutive IL-36γ levels remained largely unchanged. In human keratinocytes, IL-36α mRNA was induced by HSV- ...[more]

PMID: 28724920

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Project description:The continual threat to global health posed by influenza has led to increased efforts to improve the effectiveness of influenza vaccines for use in epidemics and pandemics. We show in this study that formulation of a low dose of inactivated detergent-split influenza vaccine with a Toll-like receptor 2 (TLR2) agonist-based lipopeptide adjuvant (R4Pam2Cys) provides (i) immediate, antigen-independent immunity mediated by the innate immune system and (ii) significant enhancement of antigen-dependent immunity which exhibits an increased breadth of effector function. Intranasal administration of mice with vaccine formulated with R4Pam2Cys but not vaccine alone provides protection against both homologous and serologically distinct (heterologous) viral strains within a day of administration. Vaccination in the presence of R4Pam2Cys subsequently also induces high levels of systemic IgM, IgG1, and IgG2b antibodies and pulmonary IgA antibodies that inhibit hemagglutination (HA) and neuraminidase (NA) activities of homologous but not heterologous virus. Improved primary virus nucleoprotein (NP)-specific CD8(+) T cell responses are also induced by the use of R4Pam2Cys and are associated with robust recall responses to provide heterologous protection. These protective effects are demonstrated in wild-type and antibody-deficient animals but not in those depleted of CD8(+) T cells. Using a contact-dependent virus transmission model, we also found that heterologous virus transmission from vaccinated mice to naive mice is significantly reduced. These results demonstrate the potential of adding a TLR2 agonist to an existing seasonal influenza vaccine to improve its utility by inducing immediate short-term nonspecific antiviral protection and also antigen-specific responses to provide homologous and heterologous immunity.The innate and adaptive immune systems differ in mechanisms, specificities, and times at which they take effect. The innate immune system responds within hours of exposure to infectious agents, while adaptive immunity takes several days to become effective. Here we show, by using a simple lipopeptide-based TLR2 agonist, that an influenza detergent-split vaccine can be made to simultaneously stimulate and amplify both systems to provide immediate antiviral protection while giving the adaptive immune system time to implement long-term immunity. Both types of immunity induced by this approach protect against vaccine-matched as well as unrelated virus strains and potentially even against strains yet to be encountered. Conferring dual functionality to influenza vaccines is beneficial for improving community protection, particularly during periods between the onset of an outbreak and the time when a vaccine becomes available or in scenarios in which mass vaccination with a strain to which the population is immunologically naive is imperative.

Dataset Information

Interleukin-36? provides protection against HSV-1 infection, but does not modulate initiation of adaptive immune responses.

Publications

Interleukin-36β provides protection against HSV-1 infection, but does not modulate initiation of adaptive immune responses.

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