Britt W

Britt W. system and reproductive organs. Commonly infected tissues included the thymus, spleen, lymph nodes, kidneys, bladder, and salivary glands. Histological examination revealed prominent nodular hyperplasia in spleens and variable levels of lymphoid lymphofollicular hyperplasia in lymph nodes. One of six inoculated animals had limited viral dissemination and shedding, with commensurately weak antibody responses to RhCMV antigens. These data suggest that long-term RhCMV infection parameters might be restricted by local innate factors and/or host immune responses in a minority Brompheniramine of primary infections. Together, we have established an oral RhCMV infection model that mimics natural HCMV infection. The virological and immunological parameters characterized in this study will greatly inform HCMV vaccine designs for human immunization. IMPORTANCE Human cytomegalovirus (HCMV) is globally ubiquitous with high seroprevalence rates in all communities. HCMV infections can occur vertically following mother-to-fetus transmission across the placenta and horizontally following shedding of virus in bodily fluids in HCMV-infected hosts and subsequent exposure of susceptible individuals to virus-laden fluids. Intrauterine HCMV Brompheniramine has long been recognized as an infectious threat to fetal growth and development. Since vertical HCMV infections occur Brompheniramine following horizontal HCMV transmission to the pregnant mother, the nonhuman primate model of HCMV pathogenesis was used to characterize the virological and immunological parameters of infection following primary mucosal exposures to rhesus cytomegalovirus. KEYWORDS: cytomegalovirus, mucosal pathogens, nonhuman primate, rhesus, shedding, viral immunity, viral pathogenesis INTRODUCTION Human cytomegalovirus (HCMV) infection is globally ubiquitous, and infection outcomes are usually either subclinical or mild and self-limiting in immunocompetent individuals (1). However, HCMV is a significant cause of morbidity and mortality in those without fully functional immune systems, including immunosuppressed transplant recipients and those coinfected with HIV who are not on antiretroviral chemotherapy (2,C4). Notably, HCMV is also the most frequent congenital infection, with a global birth prevalence of 0.64% (5) and locale-specific frequencies ranging from 0.3 to 5 5.4% (6). Congenital HCMV can disrupt fetal growth and development (7), and postnatal sequelae, which can range from mild to severe, have been estimated to occur in 10 to 15% of congenital infections (8,C11). Since the preponderance of congenital outcomes entail permanent neurological damage, including cognitive impairments and sensorineural hearing loss (12), the annual global burden of congenital HCMV infection is enormous. Based on an estimated 135 million global live births in 2019 (13), a global congenital infection rate of 0.64% (10) would equate to 864,000 congenital infections each year. Although therapeutics are available for clinically apparent neonatal infections, expeditious use of a protective vaccine strategy remains the best prevention option. Clinical trials have shown that treatment of children, symptomatic at birth with congenital HCMV, with intravenous ganciclovir or oral valganciclovir can improve long-term hearing and neurological outcomes, although there can be drug-related adverse effects (14, 15). Development of a vaccine that protects fetuses from congenital HCMV infection and its sequalae has been a long-held health priority (7), and Brompheniramine the quest for an effective HCMV vaccine has been ongoing for more than 4 decades (16). However, a licensed vaccine remains an unfulfilled objective, attributable in part to the complexity of HCMV pathogenesis, incompletely defined correlates of host protective immunity, HCMV immune evasion, and species-specific barriers to evaluating direct HCMV infection and immunology in tractable animal models (6, 8, 9, 17, 18). Moreover, gaps remain in the understanding of HCMV natural Foxd1 history that, if filled, could lead to optimized vaccine approaches. In particular, horizontal transmission of HCMV is mediated by shedding of infectious virions in bodily fluids (e.g., saliva, urine, breast milk) and subsequent exposure of mucosal surfaces to those virus-laden fluids Brompheniramine (19). The primary goal of this study was to develop an animal model to characterize.