Oropuche Virus—An Emerging Pathogen With Escalating Risk for Outbreaks of Human Infection

Oropouche virus (OROV) is an orthobunyavirus endemic to Central and South America, with cases having been reported in Brazil, Bolivia, Colombia, Cuba, Peru, and the Dominican Republic since its original discovery in 1955 [1]. It has caused more than 30 outbreaks of ~100 000 cumulative infections since its surveillance began in 1961 [2-4] but this has likely been underestimated due to a lack of available testing in the endemic regions [5]. Its public recognition has recently spiked [6] due to an outbreak beginning in late 2023 [3, 7, 8] that has resulted in 10 275 cases and two deaths as of November 2024 [9], which are notably the first recorded deaths due to OROV infection [10]. The patients (women between 20 and 25 years old) each progressed to critical condition 4 days after initially seeking medical attention for nonspecific symptoms [11]. Indeed, OROV disease manifestations are often characterized by the development of a relatively nonspecific febrile illness after an incubation period of 3–10 days. In some rare and severe cases, however, the disease can progress to include symptoms affecting the central nervous system (CNS) at about 7–10 days post symptom onset [12]. The cellular receptor responsible for OROV viral entry has not yet been found, and host tropism remains incompletely described. However, an initial study in immunodeficient mice implicated hepatocytes as an important site for viral replication and pathogenesis, and robust viral replication was observed in primary mouse fibroblasts that were independent of interferon signaling [13]. OROV may also be maintained at low levels in interferon-expressing immune cells, as demonstrated by infection of primary mouse dendritic cells and macrophages [13] and human peripheral blood mononuclear cells (PBMCs) [14]. There are currently no antiviral treatments or vaccines available against OROV infection largely because of its status as a traditionally neglected tropical disease, which has resulted in limited tools for studying OROV including the lack of a reverse genetics system [15]. Preclinical testing has so far resulted in the identification of target epitopes [16, 17] and the development of a vaccine candidate [18], but has also suggested that the broad antiviral pharmaceuticals ribavirin and mycophenolic acid may not be effective against OROV infection [11]. The public attention raised by the recent OROV outbreak has illuminated several features about OROV that raise its potential for additional outbreaks and wider spread to other non-endemic regions. OROV is primarily transmitted by the midge Culicoides paraensis, which is found in urban and rural settings, and is suspected to infect a wide range of animal hosts as indicated by its seropositivity in birds, sloths, rodents, and nonhuman primates that are local to the affected areas. Genomic analysis from the 2023-2024 outbreak demonstrates a geographic segregation of virus clades [19, 20] that have been modeled to be consistent with vector dissemination events of short-range migrations (consistent with insects) throughout the 2010s up to the current outbreak [20]. OROV has also been identified in a human (Ecuadorian) patient outside the known range of C. paraensis, raising the possibility for transmission by other insect vector(s). The potential diverse range of OROV transmission vector(s), combined with increased human contact with insects in endemic areas due to factors such as deforestation and climate change [21], highlights its risk for spreading into previously unaffected areas. Human-to-human contact has thus far not been definitively shown for OROV transmission. Cases in the Amazonian region of Brazil during the 2023–2024 outbreak have been found to be approximately 4 times higher in smaller municipalities than larger ones, suggesting that proximity and environmental conditions favoring contact with the virus-carrying vectors may be the biggest contributor to disease spread [20]. Furthermore, 21 cases of OROV infection have been identified in American travelers returning from Cuba, but no instances of further, local spread have been documented from those infected individuals [22]. However, OROV has recently been identified in semen by RT-PCR in a travel-acquired case that appears to persist up to 58-day post-symptom onset [23]. Vertical transmission is, therefore, being considered as a possible OROV dissemination route, with several noted clinical cases in Brazil with OROV RT-PCR positivity in children presenting with microcephaly or fetal death and in their mothers [24], although concrete evidence for congenital transmissions has not been shown. OROV IgM and positive hemagglutination tests (but not viral RNA) have been identified in 4 historical cases of microcephaly with unknown cause taken from 2014 to 2018 [3]. These recent findings highlight the possibility for human-to-human transmissions of OROV, but this needs further investigation. Finally, genetic and phylogenetic analyses of OROV have identified evolutionary patterns comparable to other viral pathogens with breakout strains in human hosts [25, 26]. The OROV small (S) genomic segment (which encodes the nucleocapsid protein and a nonstructural protein) and the large (L) segment (which encodes the RNA-dependent RNA polymerase) were found to have a higher historical evolutionary rate than the medium (M) segment encoding the membrane protein complex [27]. This indicates that viral RNA synthesis that is dependent on the viral polymerase gene product encoded on the L segment as well as the nucleoprotein and nonstructural protein that regulates host immune signaling on the S segment might act as stronger evolutionary drivers than viral entry that is mediated by the membrane protein encoded on the M segment, which has been suggested for other viruses with a similar segmented viral genomic structure that can infect multiple hosts [25, 26]. The OROV segmented genome has also been shown to mediate genomic reassortment that is similar to a well-documented method of viral evolution for influenza [28]. The current OROV outbreak strain is a reassortment strain that contains the M segment(s) originating in the eastern Amazon and the L and S segments found in Peru, Colombia, and Ecuador [20]. Differences in the estimated time of the most recent common ancestor of each OROV strain might also indicate historical genomic reassortment events [27], and several OROV isolates have been identified as reassortants [11, 29-32]. These recent developments highlight the urgency for enhanced surveillance and further studies of OROV transmission routes and its disease management and prevention. The range for known OROV insect vector(s) and other putative transmission vector(s) and potential intermediate host(s) extend beyond the current range of reported cases (including into the Southern USA), with one study estimating that 2–5 million Americans are at risk of exposure to OROV [33]. Recent compelling evidence suggestive of potential vertical transmission of OROV and the continued OROV detections and spreads are alarming and required continuing surveillance. Along with efforts to further develop targeted therapeutics and comparative animal models for OROV infection [11] to understand its disease pathology and pathogenesis, rapid surveillance will be critical for this emerging and historically neglected viral pathogen with pandemic potential. Morgan Brisse was supported [in part] by the Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health. The authors have nothing to report. The authors declare no conflicts of interest. The authors have nothing to report.