Research Article: Association of Symptoms and Severity of Rift Valley Fever with Genetic Polymorphisms in Human Innate Immune Pathways

Date Published: March 10, 2015

Publisher: Public Library of Science

Author(s): Amy G. Hise, Zachary Traylor, Noémi B. Hall, Laura J. Sutherland, Saidi Dahir, Megan E. Ermler, Samuel Muiruri, Eric M. Muchiri, James W. Kazura, A. Desirée LaBeaud, Charles H. King, Catherine M. Stein, Kenji Hirayama.

Abstract: BackgroundMultiple recent outbreaks of Rift Valley Fever (RVF) in Africa, Madagascar, and the Arabian Peninsula have resulted in significant morbidity, mortality, and financial loss due to related livestock epizootics. Presentation of human RVF varies from mild febrile illness to meningoencephalitis, hemorrhagic diathesis, and/or ophthalmitis with residual retinal scarring, but the determinants for severe disease are not understood. The aim of the present study was to identify human genes associated with RVF clinical disease in a high-risk population in Northeastern Province, Kenya.Methodology/Principal FindingsWe conducted a cross-sectional survey among residents (N = 1,080; 1–85 yrs) in 6 villages in the Sangailu Division of Ijara District. Participants completed questionnaires on past symptoms and exposures, physical exam, vision testing, and blood collection. Single nucleotide polymorphism (SNP) genotyping was performed on a subset of individuals who reported past clinical symptoms consistent with RVF and unrelated subjects. Four symptom clusters were defined: meningoencephalitis, hemorrhagic fever, eye disease, and RVF-not otherwise specified. SNPs in 46 viral sensing and response genes were investigated. Association was analyzed between SNP genotype, serology and RVF symptom clusters. The meningoencephalitis symptom phenotype cluster among seropositive patients was associated with polymorphisms in DDX58/RIG-I and TLR8. Having three or more RVF-related symptoms was significantly associated with polymorphisms in TICAM1/TRIF, MAVS, IFNAR1 and DDX58/RIG-I. SNPs significantly associated with eye disease included three different polymorphisms TLR8 and hemorrhagic fever symptoms associated with TLR3, TLR7, TLR8 and MyD88.Conclusions/SignificanceOf the 46 SNPs tested, TLR3, TLR7, TLR8, MyD88, TRIF, MAVS, and RIG-I were repeatedly associated with severe symptomatology, suggesting that these genes may have a robust association with RVFV-associated clinical outcomes. Studies of these and related genetic polymorphisms are warranted to advance understanding of RVF pathogenesis.

Partial Text: Rift Valley fever virus (RVFV) is a negative strand RNA virus of the family Bunyaviridae. Episodic epidemics of Rift Valley Fever (RVF) present a significant natural threat to human health in many countries of Africa and the Middle East, causing retinitis, encephalitis and hemorrhagic fever [1,2]. Epizootics of RVFV also seriously affect livestock, including sheep, cattle, goats, buffalo, and camels, creating serious economic disruption and risk of famine [3]. Two of the largest RVF outbreaks have occurred in Kenya over the last decade, the first in 1997–98 [4], and another more recently in 2006–2007 [5]. Both epidemic human disease, (including hemorrhagic fever), and enzootic livestock disease, (including excess mortality and miscarriage), are most prevalent in semi-arid areas that experienced prolonged excess rainfall during El Nino-Southern Oscillation (ENSO) weather anomalies [6]. Given the recent US experience with West Nile Virus, we could expect that, after either accidental or intentional introduction, RVFV will have the potential to become a widespread multi-state or multinational problem in North America.

In this study we examined polymorphisms in human genes of the innate immune system using diverse approaches and demonstrated association with a variety of clinical phenotypes in an ethnically Somali population of long-term residents in a RVFV endemic area. Our analysis included documentation of symptom recall using a structured interview administered by trained study personnel and we acknowledge that there may be inaccuracies with self-reported symptoms including memory lapses, selective recall of more severe symptomatology and other potential biases which are difficult to control in a retrospective study of this nature. Additional epidemiological factors associated with seropositivity and with severity of disease in this population are described elsewhere [11]. We analyzed a total of 46 SNPs in 16 genes (CFH, IL6, IL6R, IFIH1, DDX58, DHX58, MAVS, CCR5, TLR3, TLR7, TLR8, MYD88, TICAM1, IFNB, IFNAR1 CD209), and have identified innate immunity pathways that may play an important role in the pathogenesis of clinical RVF associated symptoms. These genes included those for the RNA helicases RIG-I (DDX58), LGP2 (DHX58) and their common adaptor MAVS (also called IPS-1) as well as endosomal Toll-like receptors TLR3, TLR7 and TLR8 and their signaling adaptors MyD88 and TRIF.



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