The Activated Macrophage – A Tough Fortress for Virus Invasion: How Viruses Strike Back

Macrophages (Mφ) are innate immune cells with a variety of functional phenotypes depending on the cytokine microenvironment they reside in. Mφ exhibit distinct activation patterns that are found within a wide array of activation states ranging from the originally discovered classical pro-inflammatory (M1) to the anti-inflammatory (M2) with their multi-facades. M1 cells are induced by IFNγ + LPS, while M2 are further subdivided into M2a (IL-4), M2b (Immune Complex) and M2c (IL-10) based on their inducing stimuli. Not surprisingly, Mφ activation influences the outcome of viral infections as they produce cytokines that in turn activate cells of the adaptive immune system. Generally, activated M1 cells tend to restrict viral replication, however, influenza and HIV exploit inflammation to support their replication. Moreover, M2a polarization inhibits HIV replication at the post-integration level, while HCMV encoded hrIL-10 suppresses inflammatory reactions by facilitating M2c formation. Additionally, viruses such as LCMV and Lassa Virus directly suppress Mφ activation leading to viral chronicity. Here we review how Mφ activation affects viral infection and the strategies by which viruses manipulate Mφ polarization to benefit their own fitness. An understanding of these mechanisms is important for the development of novel immunotherapies that can sway Mφ phenotype to inhibit viral replication.

A GIS-BASED APPROACH TO RISK MAPPING OF LASSA FEVER OUTBREAK IN AKURE SOUTH LOCAL GOVERNMENT AREA, NIGERIA

Lassa fever is an acute viral illness, which is endemic in some counties in West Africa, including Guinea, Liberia, Sierra Leone and parts of Nigeria. It is caused by the Lassa virus, which is primarily hosted by multi-mammate rats that live in and around houses. This study sees the need to enhance public awareness by producing risk maps of Lassa fever for the study area. In a bid to understand and predict the prevalence of the disease in Akure South Local Government Area. Temporal and spatial analyses of Lassa fever cases were carried out, information about related environmental variables such as temperature, rainfall, vegetation, and elevation were obtained. These data sets from primary and secondary sources were integrated independently as predictor variables for the developed risk model. The accessibility of incidences of Lassa fever to health centres was determined and analysed. The risk map produced indicates that areas about the Ijoka community are at higher risk of being affected by a future Lassa fever outbreak than other areas. The model developed an understanding of the high risk and potential outbreak of Lassa fever to alert the general public of the virus to curb the future outbreak. However, future research can be on the control and prevention of Lassa fever in the study area.

Statistical Distribution of Lassa Fever in Edo State, Nigeria

Lassa fever is a severe viral infection caused by the Lassa virus and spread by contact with excretions or secretions of infected rats gaining access to food and water inside human houses and other human activity areas. Sierra Leone, the Republic of Guinea, Nigeria, and Liberia are among the nations where it is endemic with a high number of deaths recorded yearly due to Lassa fever. In Nigeria, one of the states with the highest incidence is Edo. In order to reduce and predict the spread of Lassa fever in Edo state, the trend of the disease needs to be understood. Knowledge of the statistical distribution of a disease is one of the best ways to understand the trend of the disease. Currently, existing research on the statistical distribution of Lassa fever is very rare. The present work is an attempt to initiate research on the statistical distribution of Lassa fever with data obtained on weekly cases of Lassa Fever in Edo State, Nigeria. Based on the Kolmogorov Smirnoff and Anderson Darling’s goodness of fit test for fitting distribution, the Geometric distribution outfitted the weekly confirmed incidences of Lassa fever in Edo State, Nigeria when compared with the Discrete Uniform and Poisson distributions. The study further revealed that on the average, two Lassa fever cases is recorded per week in Edo State within the study period. This number of cases per week is on the high side and should be immediately looked into.

Conformational changes in Lassa virus L protein associated with promoter binding and RNA synthesis activity

Lassa virus is endemic in West Africa and can cause severe hemorrhagic fever. The viral L protein transcribes and replicates the RNA genome via its RNA-dependent RNA polymerase activity. Here, we present nine cryo-EM structures of the L protein in the apo-, promoter-bound pre-initiation and active RNA synthesis states. We characterize distinct binding pockets for the conserved 3’ and 5’ promoter RNAs and show how full-promoter binding induces a distinct pre-initiation conformation. In the apo- and early elongation states, the endonuclease is inhibited by two distinct L protein peptides, whereas in the pre-initiation state it is uninhibited. In the early elongation state, a template-product duplex is bound in the active site cavity together with an incoming non-hydrolysable nucleotide and the full C-terminal region of the L protein, including the putative cap-binding domain, is well-ordered. These data advance our mechanistic understanding of how this flexible and multifunctional molecular machine is activated.

Projecting vaccine demand and impact for emerging zoonotic pathogens

Despite large outbreaks in humans seeming improbable for a number of zoonotic pathogens, several pose a concern due to their epidemiological characteristics and evolutionary potential. To enable effective responses to these pathogens in the event that they undergo future emergence, the Coalition for Epidemic Preparedness Innovations is advancing the development of vaccines for several pathogens prioritized by the World Health Organization. A major challenge in this pursuit is anticipating demand for a vaccine stockpile to support outbreak response. We developed a modeling framework for outbreak response for emerging zoonoses under three reactive vaccination strategies. Annual vaccine regimen requirements for a population-wide strategy ranged from >670,000 (95% prediction interval: 0-3,630,000) for Lassa virus to 1,190,000 (95% PrI: 0-8,480,000) for Rift Valley fever virus, while the regimens required for ring vaccination or targeting healthcare workers (HCWs) were several orders of magnitude lower. For each pathogen and vaccination strategy, reactive vaccination typically prevented fewer than 10% of cases, because of their presently low R0 values. Targeting HCWs had a higher per-regimen impact than population-wide vaccination. Our framework provides a flexible methodology for estimating vaccine stockpile needs and the geographic distribution of demand under a range of outbreak response scenarios.

Differential pathogenesis of closely related 2018 Nigerian outbreak clade III Lassa virus isolates

Nigeria continues to experience ever increasing annual outbreaks of Lassa fever (LF). The World Health Organization has recently declared Lassa virus (LASV) as a priority pathogen for accelerated research leading to a renewed international effort to develop relevant animal models of disease and effective countermeasures to reduce LF morbidity and mortality in endemic West African countries. A limiting factor in evaluating medical countermeasures against LF is a lack of well characterized animal models outside of those based on infection with LASV strain Josiah originating form Sierra Leone, circa 1976. Here we genetically characterize five recent LASV isolates collected from the 2018 outbreak in Nigeria. Three isolates were further evaluated in vivo and despite being closely related and from the same spatial / geographic region of Nigeria, only one of the three isolates proved lethal in strain 13 guinea pigs and non-human primates (NHP). Additionally, this isolate exhibited atypical pathogenesis characteristics in the NHP model, most notably respiratory failure, not commonly described in hemorrhagic cases of LF. These results suggest that there is considerable phenotypic heterogeneity in LASV infections in Nigeria, which leads to a multitude of pathogenesis characteristics that could account for differences between subclinical and lethal LF infections. Most importantly, the development of disease models using currently circulating LASV strains in West Africa are critical for the evaluation of potential vaccines and medical countermeasures.

Predicting the evolution of Lassa Virus endemic area and population at risk over the next decades

Lassa fever is listed among the diseases that pose the greatest risks to public health by the World Health Organization. This severe viral hemorrhagic fever is caused by Lassa virus, a zoonotic pathogen that repeatedly spills over to humans from its rodent reservoirs. It is currently not known how climate change, transformations in land use, and human population growth could affect the endemic area of this virus, currently limited to parts of West Africa. By exploring the environmental data associated with virus occurrence, we show how temperature, precipitation and the presence of pastures determine ecological suitability for virus circulation. We project that regions in Central and East Africa will likely become suitable for Lassa virus over the next decades and estimate that the total population living in areas suitable for Lassa virus may grow from about 100 million to 700 million by 2070. By analysing geotagged viral genomes, we find that in the event of Lassa virus being introduced into a new suitable region, its spread might remain spatially limited over the first decades. Our results highlight how the endemic area of Lassa virus may expand well beyond West Africa in the next decades due to human impact on the environment, putting hundreds of million more people at risk of infection.