Surfactant Protein A Impairs Genital HPV16 Pseudovirus Infection by Innate Immune Cell Activation in A Murine Model.

Abstract: 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.

The Role of Type 2 Diabetes for the Development of Pathogen-Associated Cancers in the Face of the HIV/AIDS Epidemic.

The contribution of HIV to the development of pathogen-associated cancers has long been recognized, as has the contribution of type 2 diabetes for the development of several types of cancer. While HIV/AIDS-associated immunosuppression reduces immunosurveillance and indirectly contributes favorably to cancerogenesis, diabetes directly increases cancer development due to chronic low-grade inflammation, dysregulated glucose metabolism, hyperactivation of insulin-responsive pathways, and anti-apoptotic signaling. Pathogen-associated cancers contribute significantly to the cancer burden particularly in low- and middle-income countries. In those countries, the incidence of type 2 diabetes has increased alarmingly over the last decades, in part due to rapid changes in diet, lifestyle, and urbanization. It is likely that the HIV/AIDS epidemic and the steadily increasing rate of type 2 diabetes display synergistic effects on oncogenesis. Although this possible link has not been extensively investigated, it might become more important in the years to come not least due to the stimulating effects of antiretroviral therapy on the development of type 2 diabetes. This review provides an overview of the current understanding of pathogen- and diabetes- associated cancers with focus on geographical regions additionally burdened by the HIV/AIDS epidemic. As both HIV and carcinogenic infections as well as the onset of type 2 diabetes involve environmental factors that can be avoided to a certain extent, this review will support the hypothesis that certain malignancies are potentially preventable. Deploying effective infection control strategies together with educational policies on diet and lifestyle may in the long term reduce the burden of preventable cancers which is of particular relevance in low-resource settings.

Non-Pulmonary Immune Functions of Surfactant Proteins A and D.

Surfactant proteins A (SP-A) and D (SP-D) are established as essential components of our innate immune system for protecting the lung from pathogens and allergens. They essentially exert their protective functions by regulating pulmonary homeostasis. Both proteins are however widely expressed throughout the body, including the female reproductive tract, urinary tract, gastrointestinal tract, the eye, ear, nasal compartment, central nervous system, the coronary artery and the skin. The functions of SP-A and SP-D at these sites are a relatively underinvestigated area, but it is emerging that both SP-A and SP-D contribute significantly to the regulation of inflammation and protection from infection at these sites. This review presents our current understanding of the roles of SP-A and SP-D in non-pulmonary sites.