In silico identification of novel pre-microRNA genes in Rift valley fever virus suggest new pathomechanisms for embryo-fetal dysgenesis.

MicroRNAs (miRNAs) are small non-coding RNAs that regulate the post-transcriptional expression of target genes. Virus-encoded miRNAs play an important role in the replication of viruses, modulate gene expression in both the virus and host, and affect their persistence and immune evasion in hosts. This renders viral miRNAs as potential targets for therapeutic applications, especially against pathogenic viruses that infect humans and animals. Rift Valley fever virus (RVFV) is a mosquito-borne zoonotic RNA virus that causes severe disease in both humans and livestock. High mortality among newborn lambs and abortion storms are key characteristics of an RVF outbreak. To date, limited information is available on RVFV-derived miRNAs. In this study, computational methods were used to analyse the RVFV genome for putative pre-miRNA genes, which were then analysed for the presence of mature miRNAs. We detected 19 RVFV-encoded miRNAs and identified their potential mRNAs targets in sheep (Ovis aries), the most susceptible host. The identification of significantly enriched O. aries genes in association with RVFV miRNAs will help elucidate the molecular mechanisms underlying RVFV pathogenesis and potentially uncover novel drug targets for RVFV.

Ability of a dynamical climate sensitive disease model to reproduce historical Rift Valley Fever outbreaks over Africa.

Rift Valley Fever (RVF) is a zoonosis transmitted by Aedes and Culex mosquitoes, and is considered a priority pathogen by the WHO. RVF epidemics mostly occur in Africa and can decimate livestock herds, causing significant economic losses and posing health risks for humans. RVF transmission is associated with the occurrence of El Niño events that cause floods in eastern Africa and favour the emergence of mosquitoes in wetlands. Different risk models have been developed to forecast RVF transmission risk but very few studies have validated models at pan-African scale. This study aims to validate the skill of the Liverpool Rift Valley Fever model (LRVF) in reproducing RVF epidemics over Africa and to explore the relationship between simulated climatic suitability for RVF transmission and large-scale climate modes of variability such as the El Niño Southern Oscillation (ENSO) and the Dipole Mode Index (DMI). Our results show that the LRVF model correctly simulates RVF transmission hotspots and reproduces large epidemics that affected African countries. LRVF was able to correctly reproduce major RVF epidemics in Somalia, Kenya, Zambia and to a lesser extent for Mauritania and Senegal. The positive phases of ENSO and DMI are associated with an increased risk of RVF over the Horn of Africa, with important time lags. Following research activities should focus on the development of predictive modelling systems at different time scales.

Increasing evolution, prevalence, and outbreaks for rift valley fever virus in the process of breaking geographical barriers.

BACKGROUND: Rift valley fever (RVF) is listed as one of prioritized diseases by WHO. This study aims to describe RVF virus' landscape distribution globally, and to insight dynamics change of its evolution, prevalence, and outbreaks in the process of breaking geographical barriers. METHODS: A systematic literature review and meta-analyses was conducted to estimate RVF prevalence by hosts using a random-effect model. Molecular clock-based phylogenetic analyses were performed to estimate RVF virus nucleotide substitution rates using nucleotide sequences in NCBI database. RVF virus prevalence, nucleotide substitution rates, and outbreaks were compared before and after breaking geographical barriers twice, respectively. RESULTS: RVF virus was reported from 26 kinds of hosts covering 48 countries from 1930 to 2022. Since RVF broke geographical barriers, (1) nucleotide substitution rates significantly increased after firstly spreading out of Africa in 2000, (2) prevalence in humans significantly increased from 1.92 % (95 % CI: 0.86-3.25 %) to 3.03 % (95 % CI: 2.09-4.12 %) after it broke Sahara Desert geographical barriers in 1977, and to 5.24 % (95 % CI: 3.81-6.82 %) after 2000, (3) RVF outbreaks in humans and the number of wildlife hosts presented increasing trends. RVF virus spillover may exist between bats and humans, and accelerate viral substitution rates in humans. During outbreaks, the RVF virus substitution rates accelerated in humans. 60.00 % RVF outbreaks occurred 0-2 months after floods and (or) heavy rainfall. CONCLUSION: RVF has the increasing risk to cause pandemics, and global collaboration on "One Health" is needed to prevent potential pandemics.

Participatory survey of risk factors and pathways for Rift Valley fever in pastoral and agropastoral communities of Uganda.

To assess pastoralists' and agropastoralists' knowledge on Rift Valley fever (RVF), participatory epidemiological studies were conducted with 215 livestock keepers and 27 key informants in Napak, Butebo, Isingiro and Lyantonde districts, Uganda, between January and February 2022. Livestock keepers in all four districts had knowledge of RVF and even had local names or descriptions for it. Pastoralists and agropastoralists possessed valuable knowledge of RVF clinical descriptions and epidemiological risk factors such as the presence of infected mosquitoes, living in flood-prone areas, and excessive rainfall. RVF was ranked among the top ten most important cattle diseases. Pastoralists called RVF Lonyang, symbolizing a disease associated with jaundice, high fever, abortions in pregnant cows, and sudden death in calves. Key informants identified infected domestic animals, the presence of infected mosquitoes, livestock movement and trade, and infected wild animals as risk pathways for the introduction of RVF into an area. Drinking raw blood and milk was perceived as the most likely pathway for human exposure to RVF virus; while the highest consequence was high treatment costs. The results indicate that pastoralists provided key epidemiological information that could be essential for designing an effective national RVF surveillance and early warning system.

The increasing threat of Rift Valley fever virus globalization: strategic guidance for protection and preparation.

Rift Valley fever virus (RVFV) (Bunyavirales: Phlebovirus) is a prominent vector-borne zoonotic disease threat to global agriculture and public health. Risks of introduction into nonendemic regions are tied to changing climate regimes and other dynamic environmental factors that are becoming more prevalent, as well as virus evolutionary factors and human/animal movement. Endemic to the African continent, RVFV has caused large epizootics at the decadal scale since the early 20th century but has spread to the Arabian Peninsula and shows increasing patterns of interepizootic transmission on the annual scale. This virus can be transmitted by mosquitoes as well as through direct contact with infected tissues and can cause sporadic to widespread morbidity and mortality in domestic ungulate livestock as well as humans. High viremias in infected livestock moved for legal and illegal trade as well as in infected mosquitoes or human travelers can spread this virus worldwide. With increasing global commerce, it is likely RVFV will be introduced to new areas with suitable hosts, mosquito vector species, and environments. However, the strong mosquito component of RVFV epidemiology combined with advancements in vaccines, diagnostics, and virus evolutionary factors create opportunities for strategies to leverage models of connectivity among potential source and emerging regions to target surveillance and mitigation activities to reduce the risk of RVFV introduction, or contain the virus should it be introduced, into new regions.

Seroprevalence of Rift Valley Fever virus in one-humped camels (Camelus dromedaries) in Egypt.

Rift Valley fever (RVF) is a mosquito-borne viral disease that affects a variety of domestic animals, including cattle, sheep, goats, and camels, and has zoonotic potential. Although the rift valley fever virus (RVFV) is usually asymptomatic in camels, it can induce abortion in some pregnant animals. In the current study, a serosurvey was carried out to investigate the prevalence of RVFV antibodies and related risk factors in camels from four Egyptian governorates. A total of 400 serum samples were examined for anti-RVFV antibodies using a competitive enzyme-linked immunosorbent assay (c-ELISA). The results revealed that the overall prevalence of RVF among examined camels was 21.5% and the disease was more prevalent in Kafr ElSheikh governorate in Nile Delta of Egypt. In addition, the age group of camels with more than 5 years (OR=4.49, 95%CI: 1.39-14.49), the female sex (OR=3.38, 95%CI: 1.51-7.58), the emaciated animals (OR=1.52, 95%CI: 0.86-2.66), the summer season's infection (OR=5.98, 95%CI: 1.79-19.93), the presence of mosquitoes (OR= 2.88, 95%CI: 1.39-5.95), and the absence of mosquitoes control (OR=3.97, 95%CI: 2.09-7.57) were identified as risk factors for RVFV infection. The results of this study support knowledge on the risk factors for RVFV infection and demonstrate that camels raising in Egypt have RVFV antibodies. Quarantine measures or vaccination program should be implemented to reduce the likelihood of RVFV introduction, dissemination among susceptible animals, and ultimately transmission to humans.

Ecological and subject-level drivers of interepidemic Rift Valley fever virus exposure in humans and livestock in Northern Kenya.

Nearly a century after the first reports of Rift Valley fever (RVF) were documented in Kenya, questions on the transmission dynamics of the disease remain. Specifically, data on viral maintenance in the quiescent years between epidemics is limited. We implemented a cross-sectional study in northern Kenya to determine the seroprevalence, risk factors, and ecological predictors of RVF in humans and livestock during an interepidemic period. Six hundred seventy-six human and 1,864 livestock samples were screened for anti-RVF Immunoglobulin G (IgG). Out of the 1,864 livestock samples tested for IgG, a subset of 1,103 samples was randomly selected for additional testing to detect the presence of anti-RVFV Immunoglobulin M (IgM). The anti-RVF virus (RVFV) IgG seropositivity in livestock and humans was 21.7% and 28.4%, respectively. RVFV IgM was detected in 0.4% of the livestock samples. Participation in the slaughter of livestock and age were positively associated with RVFV exposure in humans, while age was a significant factor in livestock. We detected significant interaction between rainfall and elevation's influence on livestock seropositivity, while in humans, elevation was negatively associated with RVF virus exposure. The linear increase of human and livestock exposure with age suggests an endemic transmission cycle, further corroborated by the detection of IgM antibodies in livestock.

Knowledge, attitudes and practices on rift valley fever among pastoral and agropastoral communities of Ngorongoro in the rift valley ecosystem, Tanzania, conducted in 2021/2022.

Epidemics of Rift Valley fever (RVF), a mosquito-borne zoonotic disease caused by RVF virus, have been linked to exceptionally heavy rainfall and widespread flooding. The disease is endemic in most African countries and pose a major global health risk. Given that the disease was reported in various districts of Tanzania, we hypothesized a lack of knowledge about RVF epidemiology among agropastoral and pastoral communities. The research took place in a period of 7 months, from July, 2021 to January, 2022. The aim of this study was to assess the knowledge, attitudes, and practices (KAP) among the agropastoral and pastoral communities of Ngorongoro district towards RVF. The survey employed a mixed method system, which included 3 focus groups (each comprised 12 individuals), 20 key informant interviews and administration of questionnaire (N = 352) in agropastoral and pastoral community members of Ngorongoro district. The relationship between demographic characteristics and communities' knowledge, attitudes, and practices regarding RVF was observed using a multiple logistic regression model. A total of 352 participants were interviewed, with the majority (67.61%) being male and 32.39% being female, majority (39.5%) attending primary school, and majority (58.2%) being pastoralists. The findings showed that only 36.1%, 38.64% and 16.19% of participants had good knowledge, positive attitude and good practices regarding RVF respectively. Significant demographic factors related with knowledge included: gender (OR = 1.9, CI = 1.03-3.56, P = 0.041), education levels (primary: OR = 3.97, CI = 2-8.16, P = 0.000; secondary: OR = 15.27, CI = 5.5-46.23, P = 0.000 and college: OR = 34. 23, CI = 5.4-67.22, P = 0.000), and locality (Pinyinyi: OR = 0.14, CI = 0.05-0.38, P = 0.000 and Sale: OR = 0.14, CI = 0.04-0.44, P = 0.001). Male participants showed significant positive attitude towards RVF compared to female (OR = 2.37, CI = 1.35-4.17, P = 0.003). Individuals with formal education showed a significant positive attitude toward RVF compared to informal (OR>1, P<0.05). Agropastoral members showed a significant negative attitude toward RVF compared to pastoralists (OR = 0.51, CI = 0.26-0.99, P = 0.048). The calculated RVF prevention practices values were insignificantly (P = 0.853) correlated with knowledge values. The significant correlation between knowledge and attitude, as well as attitude and practice were found (P<0.05). In general, the study revealed poor knowledge, negative attitude and poor practices of communities towards RVF. The lack of regular education programs to make the communities aware of the disease was implicated for these findings. This recommends that provision of health education should be a long-term practice among agropastoral and pastoral communities in order to prevent further RVF outbreaks in Tanzania.

Contemporary epidemiological data of Rift Valley fever virus in humans, mosquitoes and other animal species in Africa: A systematic review and meta-analysis.

Rift Valley fever (RVF) is a severe zoonotic mosquito-borne disease that represents an important threat to human and animal health, with major public health and socioeconomic impacts. This disease is endemic throughout many African countries and the Arabian Peninsula. This systematic review with meta-analysis was conducted to determine the RVF prevalence in humans, mosquitoes and other animal species in Africa. The review also provides contemporary data on RVF case fatality rate (CFR) in humans. In this systematic review with meta-analysis, a comprehensive literature search was conducted on the PubMed, Embase, Web of Science and Global Index Medicus databases from January 2000 to June 2022 to identify relevant studies. Pooled CFR and prevalence estimates were calculated using the random-effects model. Subgroup analysis and sensitivity analysis were performed, and the I2 -statistic was used to investigate a potential source of heterogeneity. A total of 205 articles were included in the final analysis. The overall RVF CFR in humans was found to be 27.5% [95% CI = 8.0-52.5]. The overall pooled prevalence was 7.8% [95% CI = 6.2-9.6] in humans and 9.3% [95% CI = 8.1-10.6] in animals, respectively. The RVF prevalence in individual mosquitoes ranged from 0.0% to 25%. Subgroup analysis showed substantial heterogeneity with respect to geographical regions and human categories. The study shows that there is a correspondingly similar prevalence of RVF in human and animals; however, human CFR is much higher than the observed prevalence. The lack of a surveillance programme and the fact that this virus has subclinical circulation in animals and humans could explain these observations. The implementation of a One Health approach for RVF surveillance and control would be of great interest for human and animal health.

A highly potent human neutralizing antibody prevents vertical transmission of Rift Valley fever virus in a rat model.

Rift Valley fever virus (RVFV) is an emerging mosquito-transmitted virus that circulates in livestock and humans in Africa and the Middle East. Outbreaks lead to high rates of miscarriages in domesticated livestock. Women are also at risk of vertical virus transmission and late-term miscarriages. MAb RVFV-268 is a highly potent recombinant neutralizing human monoclonal antibody that targets RVFV. Here we show that mAb RVFV-268 reduces viral replication in rat placenta explant cultures and prevents vertical transmission in a rat model of congenital RVF. Passive transfer of mAb RVFV-268 from mother to fetus occurs as early as 6 h after administration and persists through 24 h. Administering mAb RVFV-268 2 h prior to RVFV challenge or 24 h post-challenge protects the dams and offspring from RVFV infection. These findings support mAb RVFV-268 as a pre- and post-infection treatment to subvert RVFV infection and vertical transmission, thus protecting the mother and offspring.

Rift Valley fever virus modulates apoptosis and immune response during infection of human astrocytes.

Rift Valley fever (RVF) is an arboviral disease of zoonotic origin that causes recurrent epidemics in Africa, the Arabic Peninsula, and islands of the South West of the Indian Ocean. RVF occurs mainly in livestock but also affects humans with severe clinical manifestations, including neurological disorders. However, human neuropathogenesis of Rift Valley fever virus (RVFV) is still poorly characterized. To study the interactions between RVFV and the central nervous system (CNS), we focused on RVFV infection of astrocytes, the major glial cells of the CNS that have several supporting roles including immune response regulation. We confirmed the permissiveness of astrocytes to RVFV infection and highlighted a strain-dependent infectivity. We showed that RVFV infection of astrocytes induced cell apoptosis and observed that the RVFV Non-Structural protein NSs, a known virulence factor, potentially delayed apoptosis by sequestrating activated-caspase 3 in the nucleus. Our study also showed that RVFV-infected astrocytes upregulated expression of genes associated with inflammatory and type I interferon responses at the mRNA level, but not at the protein level. This inhibition of immune response is potentially due to a NSs-dependent mechanism of mRNA nuclear export inhibition. Together, these results highlighted the direct impact of RVFV infection on the human CNS through the induction of apoptosis and a possible inhibition of early-onset immune responses that are crucial for the host survival.

Seroprevalence and associated risk factors of brucellosis, Rift Valley fever and Q fever among settled and mobile agro-pastoralist communities and their livestock in Chad.

Brucellosis, Rift Valley fever (RVF) and Q fever are zoonoses prevalent in many developing countries, causing a high burden on human and animal health. Only a few studies are available on these among agro-pastoralist communities and their livestock in Chad. The objective of our study was to estimate brucellosis, RVF and Q fever seroprevalence among Chadian agro-pastoralist communities and their livestock, and to investigate risk factors for seropositivity. We conducted a multi-stage cross-sectional serological survey in two rural health districts, Yao and Danamadji (966 human and 1041 livestock (cattle, sheep, goat and equine) samples)). The true seroprevalence were calculated applying a Bayesian framework to adjust for imperfect diagnostic test characteristics and accounting for clustering in the study design. Risk factors for each of the zoonotic diseases were estimated using mixed effects logistic regression models. The overall prevalence for brucellosis, Q fever and RVF combined for both regions was estimated at 0.2% [95% credibility Interval: 0-1.1], 49.1% [%CI: 38.9-58.8] and 28.1% [%CI: 23.4-33.3] in humans, and 0.3% [%CI: 0-1.5], 12.8% [%CI: 9.7-16.4] and 10.2% [%CI: 7.6-13.4] in animals. Risk factors correlating significantly with the respective disease seropositivity were sex for human brucellosis, sex and Q fever co-infection for animal brucellosis, age for human Q fever, species and brucellosis co-infection for animal Q fever, age and herd-level animal RVF seroprevalence within the same cluster for human RVF, and cluster-level human RVF seroprevalence within the same cluster for animal RVF. In Danamadji and Yao, Q fever and RVF are notably seroprevalent among agro-pastoralist human and animal communities, while brucellosis appears to have a low prevalence. Correlation between the seroprevalence between humans and animals living in the same communities was detected for RVF, highlighting the interlinkage of human and animal transmissible diseases and of their health, highlighting the importance of a One Health approach.

Detection of Sporadic Outbreaks of Rift Valley Fever in Uganda through the National Viral Hemorrhagic Fever Surveillance System, 2017-2020.

Rift Valley fever (RVF) is a zoonotic disease of public health and economic importance. Uganda has reported sporadic outbreaks of RVF in both humans and animals across the country, especially in the southwestern part of the "cattle corridor" through an established viral hemorrhagic fever surveillance system. We report 52 human cases of laboratory-confirmed RVF from 2017 to 2020. The case fatality rate was 42%. Among those infected, 92% were males and 90% were adults (≥ 18 years). Clinical symptoms were characterized by fever (69%), unexplained bleeding (69%), headache (51%), abdominal pain (49%), and nausea and vomiting (46%). Most of the cases (95%) originated from central and western districts that are part of the cattle corridor of Uganda, where the main risk factor was direct contact with livestock (P = 0.009). Other predictors of RVF positivity were determined to be male gender (P = 0.001) and being a butcher (P = 0.04). Next-generation sequencing identified the predominant Ugandan clade as Kenya-2, observed previously across East Africa. There is need for further investigation and research into the effect and spread of this neglected tropical disease in Uganda and the rest of Africa. Control measures such as promoting vaccination and limiting animal-human transmission could be explored to reduce the impact of RVF in Uganda and globally.

Geostatistical Modeling and Prediction of Rift Valley Fever Seroprevalence among Livestock in Uganda.

Uganda reported cases of Rift Valley fever virus (RVFV) for the first time in almost 50 years in 2016, following an outbreak of Rift Valley fever (RVF) that caused four human infections, two of which resulted in death. Subsequent outbreak investigation serosurveys found high seroprevalence of IgG antibodies without evidence of acute infection or IgM antibodies, suggesting the possibility of undetected RVFV circulation prior to the outbreak. After the 2016 outbreak investigation, a serosurvey was conducted in 2017 among domesticated livestock herds across Uganda. Sampling data were incorporated into a geostatistical model to estimate RVF seroprevalence among cattle, sheep, and goats. Variables resulting in the best fit to RVF seroprevalence sampling data included annual variability in monthly precipitation and enhanced vegetation index, topographic wetness index, log human population density percent increase, and livestock species. Individual species RVF seroprevalence prediction maps were created for cattle, sheep, and goats, and a composite livestock prediction was created based on the estimated density of each species across the country. Seroprevalence was greater in cattle compared with sheep and goats. Predicted seroprevalence was greatest in the central and northwestern quadrant of the country, surrounding Lake Victoria, and along the Southern Cattle Corridor. We identified areas that experienced conditions conducive to potential increased RVFV circulation in 2021 in central Uganda. An improved understanding of the determinants of RVFV circulation and locations with high probability of elevated RVF seroprevalence can guide prioritization of disease surveillance and risk mitigation efforts.

Bilateral macular retinitis in patients with presumed rift valley fever from Sudan: A case series.

BACKGROUND: Epidemic retinitis occurs seasonally following febrile infections in endemic regions. Rift valley fever (RVF) is endemic to Sudan, with a recent outbreak starting in 2019. METHODS: Retrospective case series of 3 patients travelling from Sudan with post-febrile retinitis, and with a history and clinical picture suggestive of RVF retinitis. RESULTS: The three patients were adult males with underlying medical conditions and underwent fundus fluorescein angiography that confirmed bilateral retinitis and occlusive vasculitis involving the posterior pole. Optical coherence tomography showed distortion of the macular layers. Case 2 presented 1 month following febrile illness and had retinal thinning, with optical coherence tomography angiography showing marked reduction in vessel density. CONCLUSION: We present multimodal imaging data of three cases with presumed RVF retinitis from a recent outbreak in Sudan. The unavailability of standardized methods of testing for RVF, as is the case for most epidemic retinitis-causing pathogens, makes the diagnosis challenging.