Surfactant protein a impairs genital HPV16 pseudovirus infection by innate immune cell activation in a murine model

Infection by oncogenic human papillomavirus (HPV) is the principle cause of cervical cancer and other anogenital cancers. The majority of cervical cancer cases occur in low- and middle-income countries (LMIC). Prophylactic vaccines exist to combat HPV infection but accessibility to these in LMIC is limited. Alternative preventative measures against HPV infection are therefore also needed to control cervical cancer risk. HPV employs multiple mechanisms to evade the host immune response. Therefore, an approach to promote HPV recognition by the immune system can reduce infection. Surfactant proteins A and D (SP-A and SP-D) are highly effective innate opsonins of pathogens. Their function is primarily understood in the lung, but they are also expressed at other sites of the body, including the female reproductive tract (FRT). We hypothesized that raised levels of SP-A and/or SP-D may enhance immune recognition of HPV and reduce infection. Co-immunoprecipitation and flow cytometry experiments showed that purified human SP-A protein directly bound HPV16 pseudovirions (HPV16-PsVs), and the resulting HPV16-PsVs/SP-A complex enhanced uptake of HPV16-PsVs by RAW264.7 murine macrophages. In contrast, a recombinant fragment of human SP-D bound HPV16-PsVs weakly and had no effect on viral uptake. To assess if SP-A modulates HPV16-PsVs infection in vivo, a murine cervicovaginal challenge model was applied. Surprisingly, neither naïve nor C57BL/6 mice challenged with HPV16-PsVs expressed SP-A in the FRT. However, pre-incubation of HPV16-PsVs with purified human SP-A at a 1:10 (w/w) ratio significantly reduced the level of HPV16-PsV infection. When isolated cells from FRTs of naïve C57BL/6 mice were incubated with HPV16-PsVs and stained for selected innate immune cell populations by flow cytometry, significant increases in HPV16-PsVs uptake by eosinophils, neutrophils, monocytes, and macrophages were observed over time using SP-A-pre-adsorbed virions compared to control particles. This study is the first to describe a biochemical and functional association of HPV16 virions with the innate immune molecule SP-A. We show that SP-A impairs HPV16-PsVs infection and propose that SP-A is a potential candidate for use in topical microbicides which provide protection against new HPV infections

Impact of helminth infections on female reproductive health and associated diseases

A growing body of knowledge exists on the influence of helminth infections on allergies and unrelated infections in the lung and gastrointestinal (GI) mucosa. However, the bystander effects of helminth infections on the female genital mucosa and reproductive health is understudied but important considering the high prevalence of helminth exposure and sexually transmitted infections in low- and middle-income countries (LMICs). In this review, we explore current knowledge about the direct and systemic effects of helminth infections on unrelated diseases. We summarize host disease-controlling immunity of important sexually transmitted infections and introduce the limited knowledge of how helminths infections directly cause pathology to female reproductive tract (FRT), alter susceptibility to sexually transmitted infections and reproduction. We also review work by others on type 2 immunity in the FRT and hypothesize how these insights may guide future work to help understand how helminths alter FRT health

Surfactant Protein-D is essential for immunity to Helminth Infection

Author Summary Infections by parasitic worms are very common, and controlling them is a major medical and veterinary challenge. Very few drugs exist to treat them, and the parasites can develop resistance to these. In order to find new ways to control worm infections, understanding how our immune system responds to them is essential. Many important parasitic worm infections move through the host lung. In this study we show that a major secreted protein in the lung, Surfactant Protein D (SP-D), is essential for immunity to a parasitic worm infection. We found that this protein binds to worm larvae in the lung to help the immune system kill them. Infecting mice that do not express SP-D with worms demonstrates SP-D is important in this immune response. These mice are unable to launch an effective anti-worm immune response and have many more worms in their intestine compared to mice that do express SP-D. We also show that if we increase SP-D levels in the lung the mouse has better immunity to worms. Together this shows for the first time that SP-D is very important for immunity to worm infections

Pre-conception maternal helminth infection transfers via nursing long-lasting cellular immunity against helminths to offspring

Maternal immune transfer is the most significant source of protection from early-life infection, but whether maternal transfer of immunity by nursing permanently alters offspring immunity is poorly understood. Here, we identify maternal immune imprinting of offspring nursed by mothers who had a pre-conception helminth infection. Nursing of pups by helminth-exposed mothers transferred protective cellular immunity to these offspring against helminth infection. Enhanced control of infection was not dependent on maternal antibody. Protection associated with systemic development of protective type 2 immunity in T helper 2 (TH2) impaired IL-4R-/- offspring. This maternally acquired immunity was maintained into maturity and required transfer (via nursing) to the offspring of maternally derived TH2-competent CD4 T cells. Our data therefore reveal that maternal exposure to a globally prevalent source of infection before pregnancy provides long-term nursing-acquired immune benefits to offspring mediated by maternally derived pathogen-experienced lymphocytes. © 2019 by the Authors

Il4ra-independent vaginal eosinophil accumulation following helminth infection exacerbates epithelial ulcerative pathology of HSV-2 infection

How helminths influence the pathogenesis of sexually transmitted viral infections is not comprehensively understood. Here, we show that an acute helminth infection (Nippostrongylus brasiliensis [Nb]) induced a type 2 immune profile in the female genital tract (FGT). This leads to heightened epithelial ulceration and pathology in subsequent herpes simplex virus (HSV)-2 infection. This was IL-5-dependent but IL-4 receptor alpha (Il4ra) independent, associated with increased FGT eosinophils, raised vaginal IL-33, and enhanced epithelial necrosis. Vaginal eosinophil accumulation was promoted by IL-33 induction following targeted vaginal epithelium damage from a papain challenge. Inhibition of IL-33 protected against Nb-exacerbated HSV-2 pathology. Eosinophil depletion reduced IL-33 release and HSV-2 ulceration in Nb-infected mice. These findings demonstrate that Nb-initiated FGT eosinophil recruitment promotes an eosinophil, IL-33, and IL-5 inflammatory circuit that enhances vaginal epithelial necrosis and pathology following HSV-2 infection. These findings identify a mechanistic framework as to how helminth infections can exacerbate viral-induced vaginal pathology

Probiotic administration ameliorates helminth exacerbation of colitis

INTRODUCTION: Historically, Inflammatory Bowel Disease (IBD) was thought of as a disease of high-income countries (HIC) such as the USA, where 1-3 million people are estimated to suffer from IBD. However, as lowmiddle income countries (LMIC) become more westernized they are exposed to a number of risk factors for IBD, including diet change and smoking. Importantly, these LMIC regions also have a high burden of infectious diseases, including gastrointestinal parasite helminths that may impact on disease. Helminth infection is reported to both exacerbate and alleviate IBD, however one consensus on how helminths modify disease is lacking. METHODS: This study makes use of a well-defined model of murine colitis (IBD) and a natural parasite of mice Heligmosomoides polygyrus (H.polygyrus) to test how helminth infection alters the incidence of IBD. BALB/c mice were infected with 200 H.polygyrus L3 larvae for either 7 or 28 days. Dextran Sulfate Sodium (DSS) colitis was induced through the administration of the DSS chemical in drinking water for 7 days, after which the mice were put back on normal drinking water for 3 days. The probiotic VSL#3 was administered in drinking water ad libitum during helminth infection. RESULTS: We demonstrate that helminth infection exacerbates DSS colitis . Infection with H.polygyrus is associated with increased colon inflammation as well as increased systemic inflammation, including splenomegaly and neutrophilia. This heightened systemic inflammation is characterised by significant bacterial translocation to the spleen, significant shifts in bacterial composition and a loss in intestinal epithelial integrity. Exacerbation of DSS colitis is dependent on host gender, host specific pathogen free (SPF) status and the dose of H.polygyrus infective larvae but is independent of the phase of H.polygyrus infection. The administration of probiotics during helminth infection restored epithelial integrity, significantly reduced bacterial translocation to the spleen, ameliorated splenomegaly and reduced helminth exacerbation of DSS colitis. CONCLUSION: Our work uncovers an unexpected and novel role for live helminth infection in exacerbating IBD and suggests that helminth-induced dysbiosis of the microbiota may drive exacerbation. These studies reveal restoration of the microbiota through probiotics as a potential therapy for the treatment of gastrointestinal inflammatory disorders

Helminths and Colitis: Friends or Foes?

The mechanisms by which gastrointestinal helminths can modulate inflammatory disorders are of great scientific interest for the development of novel therapeutics to treat disease. Currently, the established literature emphasizes the protective role of helminth infection in murine models of inflammatory bowel disease (IBD). Using the gastrointestinal helminth Heligmosomoides polygyrus (H.polygyrus), we demonstrate that helminth infection exacerbates IBD in 2 different models - induced with oxazolone or dextran sulfate sodium (DSS). Helminth exacerbation of DSS colitis is dependent on host gender, host specific pathogen free (SPF) status and the dose of H.polygyrus infective larvae but is independent of the phase of H.polygyrus infection. Helminth exacerbation of disease is associated with increased inflammation in the colon as well as increased systemic inflammation, including splenomegaly and neutrophilia. This heightened systemic inflammation is characterised by significant bacterial translocation to the spleen, significant shifts in bacterial composition and a loss in intestinal epithelial integrity, following helminth infection. Administration of probiotics during helminth infection reduces helminth exacerbation of DSS colitis, restores epithelial integrity, significantly reduces bacterial translocation to the spleen and ameliorates splenomegaly. Our work uncovers an unexpected and novel role for live helminth infection in exacerbating IBD and suggests that helminth-induced dysbiosis of the microbiota may drive disease. These studies reveal restoration of the microbiota through probiotics as a potential therapy for the treatment of gastrointestinal inflammatory disorders

Helminth-driven type 2 inflammation enhances CD8+ T cell-mediated control of acute gammaherpesvirus infection

peer reviewedThe first stages of host colonisation with pathogens often determine the efficacy of their control through priming and maintenance of effective adaptive immune responses, which are essential for such control. Infection with different pathogens often occurs concurrently and a better understanding of how our immune system faces multiple aggressions with different sorts of pathogens is therefore important. In this study, we have investigated how helminth-driven Th2-type inflammation affects the control of host colonization by a gammaherpesvirus. We used in vivo imaging of murid herpesvirus 4 (MuHV-4) live infection to investigate viral replication in mice and observed that pre-exposed mice to helminth (Schistosoma mansoni or Nippostrongylus brasiliensis) better controlled lung acute infection and weight loss. The improved control of acute infection was associated with increased virus-specific effector CD8+ T cell responses in the bronchoalveolar lavage, lung, draining LN (dLN) and spleen; whereas depletion of CD8+ cells caused a loss of viral infection control irrespective of helminth exposure. Exposure to S. mansoni eggs caused increased numbers of dendritic cells (DCs), predominantly CD11b+ conventional DCs in the lung, and in the dLN, which was associated with higher numbers of antigen-loaded lung DCs migrating to the dLN after MuHV-4 infection. These results suggested that S. mansoni egg-induced inflammation might result in an improved priming of virus-specific CD8+ T cells. To address the role of type 2 inflammation, we next used interleukin 4 receptor α-chain (IL-4Rα) deficient mice exposed to S. mansoni eggs and observed the absence of both the enhanced control of viral acute infection and the increased CD8+ T cell response, suggesting that IL-4Rα signalling is involved. Collectively, we present data indicating that IL-4Rα-dependent type 2 inflammation induced in the lung by helminth exposure improves host control of acute viral infection through the induction of an increased virus-specific cytotoxic T cell effector response