West Nile Virus: Epidemiology and Clinical Features of an Emerging Epidemic in the United States*
West Nile virus (WNV) was first detected in North America in 1999 during an outbreak of encephalitis in New York City. Since then the virus has spread across North America and into Canada, Latin America, and the Caribbean. The largest epidemics of neuroinvasive WNV disease ever reported occurred in the United States in 2002 and 2003. This paper reviews new information on the epidemiology and clinical aspects of WNV disease derived from greatly expanded surveillance and research on WNV during the past six years.
[Show abstract] [Hide abstract] ABSTRACT: Background: Chemokine receptor 5 (CCR5) is hypothesized to drive the lymphocyte migration to central nervous system in flavivirus encephalitis, and the non-functional CCR5(increment)32 genetic variant was identified as a risk factor of a West Nile virus infection and of tick-borne encephalitis (TBE). We have attempted to investigate how CCR5 expression corresponds to the clinical course and severity of TBE. Methods: We have repeatedly studied CCR5 expression in 76 patients during encephalitic and convalescent TBE phase, analyzing its association with clinical features, cerebrospinal fluid (csf) pleocytosis, and concentrations of CCR5 ligands (chemokines CCL3, CCL4, and CCL5) and CCR5 genotype. Fifteen patients with neuroborreliosis, 7 with aseptic meningitis, 17 in whom meningitis/encephalitis had been excluded, and 18 healthy blood donors were studied as controls. Expression of CCR5 was measured cytometrically in blood and csf-activated Th lymphocytes (CD3+CD4+CD45RO+). Concentrations of chemokines in serum and csf were measured immunoenzymatically, and CCR5(increment)32 was detected with sequence-specific primers. Data were analyzed with non-parametric tests, and p < 0.05 was considered significant. Results: The blood expression of CCR5 did neither differ between the groups nor change in the course of TBE. The CCR5 expression in the inflammatory csf was several-fold increased in comparison with blood but lower in TBE than in neuroborreliosis. The csf concentration of CCL5 was increased in TBE, the highest in the most severe presentation (meningoencephalomyelitis) and correlated with pleocytosis. The CCR5(increment)32/wt genotype present in 7 TBE patients was associated with a decreased CCR5 expression, but enrichment of csf Th population in CCR5-positive cells and the intrathecal inflammatory response were preserved, without a compensatory increase of CCL5 expression. Conclusions: We infer CCR5 and CCL5 participate in the response to TBE virus, as well as to other neurotropic pathogens. The intrathecal response to TBE is not hampered in the bearers of a single copy of CCR5(increment)32 allele, suggesting that the association of CCR5(increment)32 with TBE may be mediated in the periphery at the earlier stage of the infection. Otherwise, a variability of the CCR5 expression in the peripheral blood lymphocytes seems not to be associated with a variable susceptibility to TBE.
- "A case of a severe viscerotropic disease after vaccination with an attenuated yellow fever vaccine has been described in a patient heterozygous for both CCR5Δ32 and a mutation in a promoter region of the CCL5 gene . CCR5Δ32 homozygocity has been linked to the increased susceptibility to West Nile virus (WNV), which is a neurotropic flavivirus related to TBEV and responsible for a similarly wide spectrum of clinical presentations, from asymptomatic through mild febrile disease to severe encephalitis [36, 37] . Epidemiologic studies have shown an increased risk of the clinically overt disease in CCR5Δ32 homozygotes infected with WNV, which has been hypothesized to result from the impaired lymphocyte influx into csf . "
[Show abstract] [Hide abstract] ABSTRACT: The dengue viruses are widespread in Brazil and are a major public health concern. Other flaviviruses also cause diseases in humans, although on a smaller scale. The city of São Paulo is in a highly urbanized area with few green spaces apart from its parks, which are used for recreation and where potential vertebrate hosts and mosquito vectors of pathogenic Flavivirus species can be found. Although this scenario can contribute to the transmission of Flavivirus to humans, little is known about the circulation of members of this genus in these areas. In light of this, the present study sought to identify Flavivirus infection in mosquitoes (Diptera: Culicidae) collected in parks in the city of São Paulo. Seven parks in different sectors of the city were selected. Monthly mosquito collections were carried out in each park from March 2011 to February 2012 using aspiration and traps (Shannon and CDC-CO2). Nucleic acids were extracted from the mosquitoes collected and used for reverse-transcriptase and real-time polymerase chain reactions with genus-specific primers targeting a 200-nucleotide region in the Flavivirus NS5 gene. Positive samples were sequenced, and phylogenetic analyses were performed. Culex and Aedes were the most frequent genera of Culicidae collected. Culex flavivirus (CxFV)-related and Aedes flavivirus (AEFV)-related nucleotide sequences were detected in 17 pools of Culex and two pools of Aedes mosquitoes, respectively, among the 818 pools of non-engorged females analyzed. To the best of our knowledge, this is the first report of CxFV and AEFV in the city of São Paulo and Latin America, respectively. Both viruses are insect-specific flaviviruses, a group known to replicate only in mosquito cells and induce a cytopathic effect in some situations. Hence, our data suggests that CxFV and AEFV are present in Culex and Aedes mosquitoes, respectively, in parks in the city of São Paulo. Even though Flavivirus species of medical importance were not detected, surveillance is recommended in the study areas because of the presence of vertebrates and mosquitoes that could act as amplifying hosts and vectors of flaviviruses, providing the required conditions for circulation of these viruses.
- "The isolation of ILHV from a wild bird captured in Tietê Ecological Park on the outskirts of São Paulo reported by Pereira et al. (2001) shows that pathogenic flaviviruses can be found on the edge of urbanized areas, a situation that could lead to viral transmission and even epdemics. Another example of the risk of arboviral transmission in urban cities is the rapid dissemination of WNV throughout America since its introduction in New York, in 1999 (Komar, 2000; Nash et al., 2001; Hayes and Gubler, 2006). Evidence of circulation of this virus has already been reported in South America (Komar and Clark, 2006; Mattar et al., 2005; Bosch et al., 2007; Diaz et al., 2008), including Brazil (Pauvolid-Corrêa et al., 2011; Melandri et al., 2012; Ometto et al., 2013; Vieira et al., 2015). "
[Show abstract] [Hide abstract] ABSTRACT: Most West Nile virus (WNV) infections are asymptomatic, but some lead to neuroinvasive disease with symptoms ranging from disorientation to paralysis and death. Evidence from animal models suggests that neuroinvasive infections may arise as a consequence of impaired immune protection. However, other data suggest that neurologic symptoms may arise as a consequence of immune mediated damage. We demonstrate that elevated immune responses are present in neuroinvasive disease by directly characterizing WNV-specific T cells in subjects with laboratory documented infections using human histocompatibility leukocyte antigen (HLA) class II tetramers. Subjects with neuroinvasive infections had higher overall numbers of WNV-specific T cells than those with asymptomatic infections. Independent of this, we also observed age related increases in WNV-specific T cell responses. Further analysis revealed that WNV-specific T cell responses included a population of atypically polarized CXCR3+CCR4+CCR6- T cells, whose presence was highly correlated with neuroinvasive disease. Moreover, a higher proportion of WNV-specific T cells in these subjects co-produced interferon-γ and interleukin 4 than those from asymptomatic subjects. More globally, subjects with neuroinvasive infections had reduced numbers of CD4+FoxP3+ Tregs that were CTLA4 positive and exhibited a distinct upregulated transcript profile that was absent in subjects with asymptomatic infections. Thus, subjects with neuroinvasive WNV infections exhibited elevated, dysregulated, and atypically polarized responses, suggesting that immune mediated damage may indeed contribute to pathogenic outcomes.
- "WNV specific T cells recognize a broad range of epitopes WNV, like other arboviruses in the Flaviridae family, contains a single-stranded RNA genome that encodes the capsid (C), envelope (E), premembrane (prM), and membrane (M) proteins, as well as seven nonstructural proteins (NS1, NS2a, NS2b, NS3, NS4a, NS4b, and NS5) that likely contribute to viral replication . We utilized a tetramer guided approach (S1 Fig) to comprehensively identify CD4 + T cells epitopes across the entire WNV proteome, utilizing peripheral blood samples from subjects with documented WNV infection (Table 1 ). "