Potential for Autoimmune Pathogenesis of Rift Valley Fever Virus Retinitis

Abstract

Abstract. Rift Valley Fever (RVF) is a significant threat to human health because it can progress to retinitis, encephalitis, and hemorrhagic fever. The timing of onset of Rift Valley Fever virus (RVFV) retinitis suggests an autoimmune origin. To determine whether RVFV retinitis is associated with increased levels of IgG against retinal tissue, we measured and compared levels of IgG against healthy human eye tissue by immunohistochemical analysis. We found that serum samples from RVFV-exposed Kenyans with retinitis (n = 8) were slightly more likely to have antibodies against retinal tissue than control populations, but the correlation was not statistically significant. Further investigation into the possible immune pathogenesis of RVFV retinitis could lead to improved therapies to prevent or treat this severe complication.Rift Valley Fever virus (RVFV) is a an emerging member of the family Bunyaviridae and genus Phlebovirus that is transmitted in sub-Saharan Africa, Egypt and the Arabian Peninsula.1,2 Transmission is most frequently detected when large epizootic/epidemic outbreaks occur after periods of unusually heavy rainfall. As such, the virus poses a threat to economic stability as well as to human health. Recent outbreaks have been documented in Saudi Arabia (2000) and the Horn of Africa (2006Africa ( -2007. 3-9The most common severe complication of human RVFV infection is retinitis. Retinal complications occur in up to 10% of those affected and can cause lasting loss of vision. 6,[10][11][12] Other severe complications can include encephalitis (8%), hepato-renal failure, 8 hepatitis, 10 and hemorrhagic fever (1%).11,13 Case-fatality rates have been reported as high as 31%, but the actual value is likely between 0.5% and 2% because a small proportion of infected persons are diagnosed, 11,13 especially those with milder disease. The onset of RVFV retinitis in humans occurs 5-14 days (mean = 8.8 days) after initial symptoms, 4 which coincides with the activation of the adaptive immune response.14 For the present study, we hypothesized that ocular complications of humans could be triggered by an antibody-mediated autoimmune reaction.To explore part of this hypothetical pathway, we used immunohistochemical (IHC) analysis of normal eye tissue to compare serum levels of IgG against retinal tissue among persons with and without RVFV retinitis. Serum samples were collected during household-based cluster surveys of residents of Masalani (2008) 5 and Sangailu (2011), North East Province, Kenya, where a RVF epidemic had occurred in [2006][2007]. The persons participated in a formal interview regarding demographics, potential viral exposures, their recent symptoms, and their vision. Complete physical examinations with vision testing and indirect ophthalmoscopic examination were performed to identify previous or current retinal inflammation.Exposure to RVFV was determined by screening serum for IgG against RVFV by enzyme-linked immunosorbent assay and confirmation with 80% plaque reduction neutralization testing as pre...

Clinical manifestations of Rift Valley fever in humans: Systematic review and meta-analysis

“…Generally, effective neutralising antibodies appear within 4–6 days following RVF infection leading to the resolution of symptoms [ 11 , 75 ]. Unfortunately, severe RVF disease forms are reported to occur in the presence of an effective humoral response [ 57 , 63 ] and in one study has been inconclusively associated with RVF induced autoimmune retinitis [ 76 ]. This autoimmune mechanism could presumably be responsible for other late manifestations in other tissues.…”

Urban risk factors for human Rift Valley fever virus exposure in Kenya

“…All samples from enrollment in the parent study were tested for anti-RVFV, anti-CHIKV, and anti-DENV IgG antibodies using in-house standardized ELISA tests. These standardized indirect in-house ELISA methods have been conducted previously from our study sites and specific methods for RVFV (4,25), CHIKV, and DENV (26,27) are described elsewhere.…”

“…We hypothesize that an urban transmission cycle of RVFV is indeed possible and that the first urban infections may not occur as a detectable outbreak, but rather through cryptic transmission from infected livestock or infected animal products. In this study, we aimed to document the human community burden of RVFV in two areas of Kenya and describe how risk factors may vary in the urban setting compared to what we have collectively learned previously about RVFV studies conducted primarily in rural areas [5,[25][26][27].…”

The challenging management of Rift Valley Fever in humans: literature review of the clinical disease and algorithm proposal

“…Unilateral or bilateral symptoms generally occur 5 to 14 days after the RVFV infection, but can be more delayed, and may include decreased visual acuity, scotoma, acute hemorrhagic conjunctivitis and retro-orbital pain [85]. The most frequent and most specific ocular lesion is a macular or paramacular retinitis [86,87]. The funduscopy by indirect ophthalmoscopy usually shows a single well demarcated necrotic lesion with ill-defined creamy-white patchy lesions of macular retinitis with hemorrhages [84].…”

“…Most of animal models for RVF do not show any ocular disease [35,57]. In a sheep model quantitative RT-PCR (qRT-PCR) was positive on eye tissues after the viremic phase [90], but retinal complications of RVF could also be caused by antibodyrelated auto-immune reactions [86].…”