Mucosal Viral Infections Research Articles

Use of a local anaesthetic and antiseptic wound formulation for the treatment of lambs naturally infected with Orf virus

Contagious ecthyma (CE) is a worldwide highly contagious zoonotic viral skin disease of sheep and goats. Treatment for Orf virus (ORFV) infection usually involves topical and oral antibiotics. An anaesthetic and antiseptic topical gel (Multisolfen® or Tri-Solfen®; MS®, Medical Ethics, Australia) has been documented as an efficacious therapy for lesions from mucosal and epithelial viral infections in ruminants. The present study tested a new treatment protocol of MS® for CE therapy on-farm in 150 lambs naturally infected with ORFV. Lambs were divided into three cohorts of 50 lambs each (C, D and E). Cohort C was treated with MS® 3 times with an interval of 3 days between treatments, cohort D was treated daily with hypochlorous acid, whilst cohort E served as untreated controls. The lambs were examined clinically every two days, weight measured weekly, with whole blood and sterile swabs from ORFV lesions collected for haematological analysis and specific ORFV PCR. Cohort C presented fewer lambs displaying ORFV-associated lesions than other cohorts at different times of the experiment. Further, lesions treated with MS® were milder compared with other cohorts. However, following cessation of therapy, most of the lambs again developed ORFV-associated lesions. No differences between cohorts were observed in weight, haematological and PCR results. These findings suggest that topical treatment with MS® is effective for CE in field conditions, especially in the first stages of the clinical course, although treatment with MS® may need to be extended a minimum of 4 weeks.

Persistent B Cell-Derived MHC Class II Signaling Is Required for the Optimal Maintenance of Tissue-Resident Helper T Cells.

Emerging studies have identified the critical roles of tissue-resident memory CD8+ T (TRM) and B (BRM) cells in the protection against mucosal viral infections, but the underlying mechanisms regulating robust development of TRM and BRM cells remain incompletely understood. We have recently shown that tissue-resident helper CD4+ T (TRH) cells, developed following influenza virus infection, function to sustain the optimal maintenance of TRM and BRM cells at the mucosal surface. In this study, we have explored the cellular and molecular cues modulating lung TRH persistence after influenza infection in C57BL/6 mice. We found that TRH cells were colocalized in tertiary lymphoid structures (TLSs) with local B cells. Abolishing TLSs or the depletion of B cells impaired lung TRH cell numbers. Of note, we found that persistent TCR signaling is needed for the maintenance of TRH cells after the clearance of infectious influenza virus. Furthermore, selective ablation of B cell-derived MHC class II resulted in partial reduction of lung TRH cell number after influenza infection. Our findings suggest that the interaction between lung-resident TRH cells and B cells, along with persistent Ag stimulation, is required to maintain TRH cells after respiratory viral infection.

MFGM-enriched whey displays antiviral activity against common pediatric viruses in vitro.

Among the most common mucosal viral infections in infants are rotavirus, one of the main causes of severe gastroenteritis in infants and children up to 5 years, and respiratory syncytial virus (RSV), one of the leading causes of lower respiratory tract infections. Both human milk and bovine milk derived factors may provide protection against mucosal viral infections. More recently, a similar activity of milk derived proteins was suggested for SARS-CoV-2. The goal of the current study was to test antiviral activity of the bovine milkfat globule membrane (MFGM) against rotavirus, RSV and SARS-CoV-2 and to further characterize MFGM-enriched whey to identify which components in MFGM-enriched whey may contribute to the inhibitory activity. The effects of MFGM-enriched whey, its whey protein isolate counterpart (WPI, obtained from the same production process) and a conventional whey protein concentrate (WPC) on rotavirus (strains Wa and SA114F), RSV (strain RSV-A2) and SARS-CoV-2 (Alpha variant) infectivity were determined using MA104 cells, human alveolar basal epithelial (A549) cells and monkey kidney (Vero E6) cells, respectively. The compounds were characterized in detail by LC-MS/MS and 31P-NMR to determine protein and phospholipid composition, respectively. Relative to its WPI counterpart, MFGM-enriched whey demonstrated a dose-dependent inhibition for both rotavirus and RSV whereas for SARS-CoV-2 inhibition was only observed at the highest concentration tested. Label-free quantification (LFQ) and intensity based absolute quantification (iBAQ) of identified proteins revealed a clear difference between MFGM-enriched whey and its controls including enrichment of known MFGM proteins and non-MFGM proteins that are enriched simultaneously, some of which have previously been demonstrated to display anti-viral activity. Although not completely absent from other whey protein preparations, MFGM-enriched whey had the highest specific and total phospholipid levels. MFGM-enriched whey displayed antiviral activity against multiple viruses of clinical importance. This study provides insights into the active components in MFGM-enriched whey and may contribute to previous clinical observations with MFGM-enriched formula demonstrating reduced respiratory and gastrointestinal infections in formula fed infants.

MOLLUSCUM CONTAGIOSUM AFFECTING THE LIPS

Molluscum contagiosum is a cutaneous and mucosal viral infection that can affect the oral cavity and lips on rare occasions. The aim of this study is to report a case of molluscum contagiosum affecting the lips. A 53-year-old female was referred for evaluation of multiple papules on the skin and lips. Oral and cutaneous examination revealed the presence of multiple yellowish papules in the skin of the shoulders and neck and in the vermillion border. Clinical diagnosis included molluscum contagiosum and impetigo and a biopsy of a lip lesion was performed under local anesthesia. Hematoxylin and eosin-stained histological slides showed a localized proliferation of the stratified squamous epithelium with keratinocytes presenting nuclear basophilic inclusions, compatible with molluscum contagiosum. The patient was submitted to surgical removal of additional lesions and remains in clinical follow-up. Molluscum contagiosum is a cutaneous and mucosal viral infection that can affect the oral cavity and lips on rare occasions. The aim of this study is to report a case of molluscum contagiosum affecting the lips. A 53-year-old female was referred for evaluation of multiple papules on the skin and lips. Oral and cutaneous examination revealed the presence of multiple yellowish papules in the skin of the shoulders and neck and in the vermillion border. Clinical diagnosis included molluscum contagiosum and impetigo and a biopsy of a lip lesion was performed under local anesthesia. Hematoxylin and eosin-stained histological slides showed a localized proliferation of the stratified squamous epithelium with keratinocytes presenting nuclear basophilic inclusions, compatible with molluscum contagiosum. The patient was submitted to surgical removal of additional lesions and remains in clinical follow-up.

Different Mechanisms Are Utilized by Coronavirus Transmissible Gastroenteritis Virus To Regulate Interferon Lambda 1 and Interferon Lambda 3 Production.

Type III interferons (IFN-λ) are shown to be preferentially produced by epithelial cells, which provide front-line protection at barrier surfaces. Transmissible gastroenteritis virus (TGEV), belonging to the genus Alphacoronavirus of the family Coronaviridae, can cause severe intestinal injuries in porcine, resulting in enormous economic losses for the swine industry, worldwide. Here, we demonstrated that although IFN-λ1 had a higher basal expression, TGEV infection induced more intense IFN-λ3 production in vitro and in vivo than did IFN-λ1. We explored the underlying mechanism of IFN-λ induction by TGEV and found a distinct regulation mechanism of IFN-λ1 and IFN-λ3. The classical RIG-I-like receptor (RLR) pathway is involved in IFN-λ3 but not IFN-λ1 production. Except for the signaling pathways mediated by RIG-I and MDA5, TGEV nsp1 induces IFN-λ1 and IFN-λ3 by activating NF-κB via the unfolded protein responses (UPR) PERK-eIF2α pathway. Furthermore, functional domain analysis indicated that the induction of IFN-λ by the TGEV nsp1 protein was located at amino acids 85 to 102 and was dependent on the phosphorylation of eIF2α and the nuclear translocation of NF-κB. Moreover, the recombinant TGEV with the altered amino acid motif of nsp1 85-102 was constructed, and the nsp1 (85-102sg) mutant virus significantly reduced the production of IFN-λ, compared with the wild strain. Compared to the antiviral activities of IFN-λ1, the administration of IFN-λ3 showed greater antiviral activity against TGEV infections in IPEC-J2 cells. In summary, our data point to the significant role of IFN-λ in the host innate antiviral responses to coronavirus infections within mucosal organs and in the distinct mechanisms of IFN-λ1 and IFN-λ3 regulation. IMPORTANCE Coronaviruses cause infectious diseases in various mammals and birds and exhibit an epithelial cell tropism in enteric and respiratory tracts. It is critical to explore how coronavirus infections modulate IFN-λ, a key innate cytokine against mucosal viral infection. Our results uncovered the different processes of IFN-λ1 and IFN-λ3 production that are involved in the classical RLR pathway and determined that TGEV nsp1 induces IFN-λ1 and IFN-λ3 production by activating NF-κB via the PERK-eIF2α pathway in UPR. These studies highlight the unique regulation of antiviral defense in the intestine during TGEV infection. We also demonstrated that IFN-λ3 induced greater antiviral activity against TGEV replication than did IFN-λ1 in IPEC-J2 cells, which is helpful in finding a novel strategy for the treatment of coronavirus infections.

Mucosal viral infection induces a regulatory T cell activation phenotype distinct from tissue residency in mouse and human tissues.

Regulatory T cells (Tregs) mediate immune homeostasis, yet also facilitate nuanced immune responses during infection, balancing pathogen control while limiting host inflammation. Recent studies have identified Treg populations in non-lymphoid tissues that are phenotypically distinct from Tregs in lymphoid tissues (LT), including performance of location-dependent roles. Mucosal tissues serve as critical barriers to microbes while performing unique physiologic functions, so we sought to identify distinct phenotypical and functional aspects of mucosal Tregs in the female reproductive tract. In healthy human and mouse vaginal mucosa, we found that Tregs are highly activated compared to blood or LT Tregs. To determine if this phenotype reflects acute activation or a general signature of vaginal tract (VT)-residency, we infected mice with HSV-2 to discover that VT Tregs express granzyme-B (GzmB) and acquire a VT Treg signature distinct from baseline. To determine the mechanisms that drive GzmB expression, we performed ex vivo assays to reveal that a combination of type-I interferons and interleukin-2 is sufficient for GzmB expression. Together, we highlight that VT Tregs are activated at steady state and become further activated in response to infection; thus, they may exert robust control of local immune responses, which could have implications for mucosal vaccine design.

Type I interferon regulates proteolysis by macrophages to prevent immunopathology following viral infection.

The ability to treat severe viral infections is limited by our understanding of the mechanisms behind virus-induced immunopathology. While the role of type I interferons (IFNs) in early control of viral replication is clear, less is known about how IFNs can regulate the development of immunopathology and affect disease outcomes. Here, we report that absence of type I IFN receptor (IFNAR) is associated with extensive immunopathology following mucosal viral infection. This pathology occurred independent of viral load or type II immunity but required the presence of macrophages and IL-6. The depletion of macrophages and inhibition of IL-6 signaling significantly abrogated immunopathology. Tissue destruction was mediated by macrophage-derived matrix metalloproteinases (MMPs), as MMP inhibition by doxycycline and Ro 28-2653 reduced the severity of tissue pathology. Analysis of post-mortem COVID-19 patient lungs also displayed significant upregulation of the expression of MMPs and accumulation of macrophages. Overall, we demonstrate that IFNs inhibit macrophage-mediated MMP production to prevent virus-induced immunopathology and uncover MMPs as a therapeutic target towards viral infections.

Association of Intestinal Microbial Dysbiosis With Chronic Obstructive Pulmonary Disease.

Normal gut flora plays various beneficial roles for the human body, including the protection against inflammatory states and mucosal viral infections. It also influences the immune system of the body. The metabolites produced by the gut bacteria control local and other systemic organs' immune functions like the lungs and brain, playing a role in their response to acute and chronic illnesses. Probiotics have shown beneficial effects on lung health. On the contrary, dysbiosis is associated with several diseases, including asthma, chronic bronchitis, emphysema, allergies, and other acute viral infections. By altering the diet of patients with respiratory diseases like patients with chronic obstructive pulmonary diseases (COPD), we may be able to mitigate their conditions. This literature review aims to discuss the mechanisms altering the gastrointestinal flora, the pathophysiology of gut and lung axis, the role of diet in gut microbe health, and the association of COPD with gut dysbiosis and peptic ulcer disease (PUD). We have extracted the data from PubMed and Google Scholar, consisting of review articles, case-control studies, and animal studies. The studies showed an association between gut microbes and different lung diseases. It is found that gut dysbiosis not only disrupts intestinal immunity but may also facilitate the development of COPD. Present studies also show an increased seroprevalence of Helicobacter pylori in patients with COPD. The strategies that can improve lung functions, especially in COPD patients, include prebiotics and probiotic supplementation to a diet more balanced than the current average American diet.

Group 1 innate lymphoid-cell-derived interferon-γ maintains anti-viral vigilance in the mucosal epithelium

The oropharyngeal mucosa serves as a perpetual pathogen entry point and a critical site for viral replication and spread. Here, we demonstrate that type 1 innate lymphoid cells (ILC1s) were the major immune force providing early protection during acute oral mucosal viral infection. Using intravital microscopy, we show that ILC1s populated and patrolled the uninfected labial mucosa. ILC1s produced interferon-γ (IFN-γ) in the absence of infection, leading to the upregulation of key antiviral genes, which were downregulated in uninfected animals upon genetic ablation of ILC1s or antibody-based neutralization of IFN-γ. Thus, tonic IFN-γ production generates increased oral mucosal viral resistance even before infection. Our results demonstrate barrier-tissue protection through tissue surveillance in the absence of rearranged-antigen receptors and the induction of an antiviral state during homeostasis. This aspect of ILC1 biology raises the possibility that these cells do not share true functional redundancy with other tissue-resident lymphocytes.

Differential expression of interferon-lambda receptor 1 splice variants determines the magnitude of the antiviral response induced by interferon-lambda 3 in human immune cells.

Type III interferons (IFN-lambdas(λ)) are important cytokines that inhibit viruses and modulate immune responses by acting through a unique IFN-λR1/IL-10RB heterodimeric receptor. Until now, the primary antiviral function of IFN-λs has been proposed to be at anatomical barrier sites. Here, we examine the regulation of IFN-λR1 expression and measure the downstream effects of IFN-λ3 stimulation in primary human blood immune cells, compared with lung or liver epithelial cells. IFN-λ3 directly bound and upregulated IFN-stimulated gene (ISG) expression in freshly purified human B cells and CD8+ T cells, but not monocytes, neutrophils, natural killer cells, and CD4+ T cells. Despite similar IFNLR1 transcript levels in B cells and lung epithelial cells, lung epithelial cells bound more IFN-λ3, which resulted in a 50-fold greater ISG induction when compared to B cells. The reduced response of B cells could be explained by higher expression of the soluble variant of IFN-λR1 (sIFN-λR1), which significantly reduced ISG induction when added with IFN-λ3 to peripheral blood mononuclear cells or liver epithelial cells. T-cell receptor stimulation potently, and specifically, upregulated membrane-bound IFNLR1 expression in CD4+ T cells, leading to greater antiviral gene induction, and inhibition of human immunodeficiency virus type 1 infection. Collectively, our data demonstrate IFN-λ3 directly interacts with the human adaptive immune system, unlike what has been previously shown in published mouse models, and that type III IFNs could be potentially utilized to suppress both mucosal and blood-borne viral infections.

IL-4 enhances interferon production by virus-infected human mast cells

IL-4 enhances interferon production by virus-infected human mast cells

Exogenous Interleukin-33 Contributes to Protective Immunity via Cytotoxic T-Cell Priming against Mucosal Influenza Viral Infection.

Influenza is an infectious respiratory illness caused by the influenza virus. Though vaccines against influenza exist, they have limited efficacy. To additionally develop effective treatments, there is a need to study the mechanisms of host defenses from influenza viral infections. To date, the mechanism by which interleukin (IL)-33 modulates the antiviral immune response post-influenza infection is unclear. In this study, we demonstrate that exogenous IL-33 enhanced antiviral protection against influenza virus infection. Exogenous IL-33 induced the recruitment of dendritic cells, increased the secretion of pro-inflammatory cytokine IL-12, and promoted cytotoxic T-cell responses in the local microenvironment. Thus, our findings suggest a role of exogenous IL-33 in the antiviral immune response against influenza infection.

Curative Medical Treatment for Acute Appendicitis without Surgical Appendectomy (Jaber Maneuver)

Clinical and Pathological evaluation Acute abdomen with a mixture of modern radiographic images, diagnostic laboratory investigations and clinical observation such as (McBurney’s triangle manifestations with rebound tenderness) [1]. All these signs suggest firmly acute appendicitis with mucosal viral or bacterial infection within the narrow lumen of appendix leading to luminal obstruction, this leads to increase the mucosal secretions, and inflammatory exudates, which increase the intraluminal pressure, obstructed lymphatic drainage. Edema and mucosal ulceration develop with bacterial transudation to the submucosa. Resolution may occur at this point either spontaneously or in response to antibiotics.

Cell-Penetrating Mx1 Enhances Anti-Viral Resistance against Mucosal Influenza Viral Infection.

Dynamin-like GTPase myxovirus resistance protein 1 (Mx1) is an intracellular anti-viral protein following the activation of type I and type III interferon signaling. Mx1 inhibits viral replication by blocking the transcription of viral RNA, and a deficiency in this protein enhances susceptibility to influenza infection. Thus, Mx1 could be another efficient target of anti-influenza therapy. To test our hypothesis, we fused poly-arginine cell-penetrating peptides to the C terminus of Mx1 (Mx1-9R) and examined the anti-viral activity of Mx1-9R in vitro and in vivo. Madin-Darby Canine Kidney epithelial cells internalized the Mx1-9R within 12 h. Pre-exposure Mx1-9R treatment inhibited viral replication and viral RNA expression in infected cells. Further, intranasal administration of Mx1-9R improved the survival of mice infected with the PR8 influenza viral strain. These data support the consideration of Mx1-9R as a novel therapeutic agent against mucosal influenza virus infection.

Colocalization of intracellular specific IgA (icIgA) with influenza virus in patients’ nasopharyngeal aspirate cells

Inhibition of viral replication by icIgA antibodies has only been observed with in vitro studies using epithelial cell lines in transwell cultures. This effect appears to involve an interaction between polymeric immunoglobulin A (pIgA) and viral particles within an intracellular compartment, since IgA is transported across polarized cells. Polyclonal guinea pig antisera against purified influenza A virus and mouse antisera prepared against Influenza A/H3N2 hemagglutinin (HA0) cleavage loop peptides, were used in confocal fluorescence microscopy to show specific staining of wild-type influenza H1N1 and H3N2 viruses in clinical specimens. The HA0 cleavage loop peptides used for intranasal immunization of mice were designed and synthesized from specific conserved regions of influenza A/H1N1 & A/H3N2 viruses. Anti-human secretory IgA antibodies were used to show co-localisation of influenza A virus and icIgA. The results showed specific immunofluorescent staining of influenza A/H3N2 (X31) (HA0 uncleaved)-infected MDCK cells and the presence of icIgA in respiratory exudate cells of infected patients. Both results confirm specific co-localisation and suggest interaction between influenza A virus and icIgA in patients’ respiratory exudate cells. Importantly, antisera to the mouse anti-HA0 cleavage site were specific for wild-type virus in clinical specimens, indicating that the conserved region of HA0 was present in the uncleaved form. Similar staining and colocalization patterns between icIgA and virus were observed with polyclonal guinea pig antisera against influenza A virus. These are the first observations of co-localization of influenza A virus and intracellular IgA in clinical specimens.Role of icIgA: This report shows the co-localization of influenza A virus HA0 and icIgA antibodies in respiratory exudate cells of patients who were culture and viral RNA positive, suggesting that icIgA directed against the conserved HA0 site may have a privileged and unique opportunity to act on immature virus and thus prevent HA0 cleavage, maturation and subsequent cycles of viral replication. The precise mechanism by which icIgA mediates intracellular viral neutralization remains to be fully elucidated.Significance: The above findings in clinical specimens would contribute strongly to our understanding of the mechanisms and kinetics of icIgA neutralization in relation to viral entry and early replication steps of mucosal viral infections. A rapid, objective and sensitive assay − by ex vivo enumeration of respiratory epithelial cells that have co-localized influenza virus and icIgA − would contribute to further mucosal immunity studies and inform the design of more effective vaccines against influenza and other viral infections transmitted via the mucosal route e.g. respiratory syncytial virus, rotavirus.

Expression of Ifnlr1 on Intestinal Epithelial Cells Is Critical to the Antiviral Effects of Interferon Lambda against Norovirus and Reovirus.

Lambda interferon (IFN-λ) has potent antiviral effects against multiple enteric viral pathogens, including norovirus and rotavirus, in both preventing and curing infection. Because the intestine includes a diverse array of cell types, however, the cell(s) upon which IFN-λ acts to exert its antiviral effects is unclear. Here, we sought to identify IFN-λ-responsive cells by generation of mice with lineage-specific deletion of the receptor for IFN-λ, Ifnlr1 We found that expression of IFNLR1 on intestinal epithelial cells (IECs) in the small intestine and colon is required for enteric IFN-λ antiviral activity. IEC Ifnlr1 expression also determines the efficacy of IFN-λ in resolving persistent murine norovirus (MNoV) infection and regulates fecal shedding and viral titers in tissue. Thus, the expression of Ifnlr1 by IECs is necessary for the response to both endogenous and exogenous IFN-λ. We further demonstrate that IEC Ifnlr1 expression is required for the sterilizing innate immune effects of IFN-λ by extending these findings in Rag1-deficient mice. Finally, we assessed whether our findings pertained to multiple viral pathogens by infecting mice specifically lacking IEC Ifnlr1 expression with reovirus. These mice phenocopied Ifnlr1-null animals, exhibiting increased intestinal tissue titers and enhanced reovirus fecal shedding. Thus, IECs are the critical cell type responding to IFN-λ to control multiple enteric viruses. This is the first genetic evidence that supports an essential role for IECs in IFN-λ-mediated control of enteric viral infection, and these findings provide insight into the mechanism of IFN-λ-mediated antiviral activity.IMPORTANCE Human noroviruses (HNoVs) are the leading cause of epidemic gastroenteritis worldwide. Type III interferons (IFN-λ) control enteric viral infections in the gut and have been shown to cure mouse norovirus, a small-animal model for HNoVs. Using a genetic approach with conditional knockout mice, we identified IECs as the dominant IFN-λ-responsive cells in control of enteric virus infection in vivo Upon murine norovirus or reovirus infection, Ifnlr1 depletion in IECs largely recapitulated the phenotype seen in Ifnlr1-/- mice of higher intestinal tissue viral titers and increased viral shedding in the stool. Moreover, IFN-λ-mediated sterilizing immunity against murine norovirus requires the capacity of IECs to respond to IFN-λ. These findings clarify the mechanism of action of this cytokine and emphasize the therapeutic potential of IFN-λ for treating mucosal viral infections.

Inflammatory monocytes require type I interferon receptor signaling to activate NK cells via IL-18 during a mucosal viral infection.

The requirement of type I interferon (IFN) for natural killer (NK) cell activation in response to viral infection is known, but the underlying mechanism remains unclear. Here, we demonstrate that type I IFN signaling in inflammatory monocytes, but not in dendritic cells (DCs) or NK cells, is essential for NK cell function in response to a mucosal herpes simplex virus type 2 (HSV-2) infection. Mice deficient in type I IFN signaling, Ifnar-/- and Irf9-/- mice, had significantly lower levels of inflammatory monocytes, were deficient in IL-18 production, and lacked NK cell-derived IFN-γ. Depletion of inflammatory monocytes, but not DCs or other myeloid cells, resulted in lower levels of IL-18 and a complete abrogation of NK cell function in HSV-2 infection. Moreover, this resulted in higher susceptibility to HSV-2 infection. Although Il18-/- mice had normal levels of inflammatory monocytes, their NK cells were unresponsive to HSV-2 challenge. This study highlights the importance of type I IFN signaling in inflammatory monocytes and the induction of the early innate antiviral response.

OASL1 deficiency promotes antiviral protection against genital herpes simplex virus type 2 infection by enhancing type I interferon production

Abstract Type I interferon (IFN) interferes with virus replication, promotes antiviral responses, and controls innate and adaptive immune responses to certain viruses. Recently, we reported that 2′-5′ oligoadenylate synthetase-like 1 (OASL1) negatively regulates type I IFN production by inhibiting the translation of the type I IFN-regulating master transcription factor, IRF7. Notably, while OASL1-deficient mice induce robust production of type I IFN and are resistant to systemic viral infection, the effects of OASL1 during localized viral infection has not been studied. To this end, we investigated the role of OASL1 during mucosal HSV-2 infection of the genital tract. Oasl1−/− mice exhibited better survival rates than wild type (WT) mice following intravaginal HSV-2 infection, and suppressed virus replication more efficiently despite comparable recruitment of effector immune cells. Moreover, Ly6Chigh monocytes, and not pDCs or other cell types, displayed enhanced production of type I IFNs in Oasl1−/− mice in response to HSV-2 infection. Furthermore, cytotoxic T cell responses including IFN-γ production were accelerated in Oasl1−/− mice after mucosal HSV-2 infection. Collectively, these results demonstrate that OASL1 deficiency promotes antiviral immunity against local mucosal viral infection and suggest that OASL1 could be a therapeutic target for treatment of HSV-2 infection of the genital mucosa.

OASL1 deficiency promotes antiviral protection against genital herpes simplex virus type 2 infection by enhancing type I interferon production.

Type I interferon (IFN) interferes with virus replication, promotes antiviral responses, and controls innate and adaptive immune responses to certain viruses. Recently, we reported that 2’–5’ oligoadenylate synthetase-like 1 (OASL1) negatively regulates type I IFN production by inhibiting the translation of the type I IFN-regulating master transcription factor, IRF7. Notably, while OASL1-deficient mice induce robust production of type I IFN and are resistant to systemic viral infection, the effects of OASL1 during localized viral infection has not been studied. To this end, we investigated the role of OASL1 during mucosal HSV-2 infection of the genital tract. Oasl1−/− mice exhibited better survival rates than wild type (WT) mice following intravaginal HSV-2 infection, and suppressed virus replication more efficiently despite comparable recruitment of effector immune cells. Moreover, Ly6Chigh monocytes, and not pDCs or other cell types, displayed enhanced production of type I IFNs in Oasl1−/− mice in response to HSV-2 infection. Furthermore, cytotoxic T cell responses including IFN-γ production were accelerated in Oasl1−/− mice after mucosal HSV-2 infection. Collectively, these results demonstrate that OASL1 deficiency promotes antiviral immunity against local mucosal viral infection and suggest that OASL1 could be a therapeutic target for treatment of HSV-2 infection of the genital mucosa.

Hematopoietic LTβR deficiency results in skewed T cell cytokine profiles during a mucosal viral infection.

The lymphotoxin signaling pathway plays an important role in the homeostasis and function of peripheral and mucosal dendritic cells, and dendritic cell-intrinsic lymphotoxin β receptor expression is required for optimal responses to opportunistic intestinal bacteria. However, it is unknown whether dendritic cell-intrinsic lymphotoxin β receptor signaling is required for responses to intestinal viral infections. We explored this question by orally administrating murine rotavirus to chimeric mice that lack lymphotoxin β receptor signaling in the myeloid compartment but retain lymphoid tissues. We found that although clearance of rotavirus was unimpaired in the lymphotoxin β receptor(-/-) → wild-type chimeric mice compared with wild-type → wild-type chimeric mice, IFN-γ-producing CD8(+) and CD4(+) T cells were significantly increased in the small intestinal lamina propria of lymphotoxin β receptor(-/-) → wild-type chimeric mice. In contrast, IL-17-producing CD4(+) T cells were reduced in lymphotoxin β receptor(-/-) → wild-type chimeric mice in the steady state, and this reduction persisted after rotavirus inoculation. In spite of this altered cytokine profile in the small intestinal lamina propria of lymphotoxin β receptor(-/-) → wild-type chimeric mice, the local production of rotavirus-specific IgA was unperturbed. Collectively, our results demonstrate that lymphotoxin β receptor signaling in radio-sensitive myeloid cells regulates the balance of IFN-γ and IL-17 cytokine production within the small intestinal lamina propria; however, these perturbations do not affect mucosal antiviral IgA responses.