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Ebolavirus species Zaire (ZEBOV) causes highly lethal hemorrhagic fever, resulting in the death of 90% of patients within days. Most information on immune responses to ZEBOV comes from in vitro studies and animal models. The paucity of data on human immune responses to this virus is mainly due to the fact that most outbreaks occur in remote areas. Published studies in this setting, based on small numbers of samples and limited panels of immunological markers, have given somewhat different results. Here, we studied a unique collection of 56 blood samples from 42 nonsurvivors and 14 survivors, obtained during the five outbreaks that occurred between 1996 and 2003 in Gabon and Republic of Congo. Using Luminex technology, we assayed 50 cytokines in all 56 samples and performed phenotypic analyses by flow cytometry. We found that fatal outcome was associated with hypersecretion of numerous proinflammatory cytokines (IL-1β, IL-1RA, IL-6, IL-8, IL-15 and IL-16), chemokines and growth factors (MIP-1α, MIP-1β, MCP-1, M-CSF, MIF, IP-10, GRO-α and eotaxin). Interestingly, no increase of IFNα2 was detected in patients. Furthermore, nonsurvivors were also characterized by very low levels of circulating cytokines produced by T lymphocytes (IL-2, IL-3, IL-4, IL-5, IL-9, IL-13) and by a significant drop of CD3+CD4+ and CD3+CD8+ peripheral cells as well as a high increase in CD95 expression on T lymphocytes. This work, the largest study to be conducted to date in humans, showed that fatal outcome is associated with aberrant innate immune responses and with global suppression of adaptive immunity. The innate immune reaction was characterized by a \"cytokine storm,\" with hypersecretion of numerous proinflammatory cytokines, chemokines and growth factors, and by the noteworthy absence of antiviral IFNα2. Immunosuppression was characterized by very low levels of circulating cytokines produced by T lymphocytes and by massive loss of peripheral CD4 and CD8 lymphocytes, probably through Fas/FasL-mediated apoptosis.

Aging is marked by a decline in tissue regeneration, posing significant challenges to an increasingly older population. Here, we investigate age-related impairments in calvarial bone healing and introduce a novel two-part rejuvenation strategy to restore youthful repair. We demonstrate that aging negatively impacts the calvarial bone structure and its osteogenic tissues, diminishing osteoprogenitor number and function and severely impairing bone formation. Notably, increasing osteogenic cell numbers locally fails to rescue repair in aged mice, identifying the presence of intrinsic cellular deficits. Our strategy combines Wnt-mediated osteoprogenitor expansion with intermittent fasting, which leads to a striking restoration of youthful levels of bone healing. We find that intermittent fasting improves osteoprogenitor function, benefits that can be recapitulated by modulating NAD + -dependent pathways or the gut microbiota, underscoring the multifaceted nature of this intervention. Mechanistically, we identify mitochondrial dysfunction as a key component in age-related decline in osteoprogenitor function and show that both cyclical nutrient deprivation and Nicotinamide mononucleotide rejuvenate mitochondrial health, enhancing osteogenesis. These findings offer a promising therapeutic avenue for restoring youthful bone repair in aged individuals, with potential implications for rejuvenating other tissues.

Chikungunya virus (CHIKV) is a worldwide emerging pathogen. In humans it causes a syndrome characterized by high fever, polyarthritis, and in some cases lethal encephalitis. Growing evidence indicates that the innate immune response plays a role in controlling CHIKV infection. We show here that CHIKV induces major but transient modifications in NK-cell phenotype and function soon after the onset of acute infection. We report a transient clonal expansion of NK cells that coexpress CD94/NKG2C and inhibitory receptors for HLA-C1 alleles and are correlated with the viral load. Functional tests reveal cytolytic capacity driven by NK cells in the absence of exogenous signals and severely impaired IFN-γ production. Collectively these data provide insight into the role of this unique subset of NK cells in controlling CHIKV infection by subset-specific expansion in response to acute infection, followed by a contraction phase after viral clearance.

Rabies is one of the oldest known zoonotic diseases, with dogs being the main reservoir for 99% of the cases of human rabies. However, wild animals may also be rabies vectors. In most cases, contact with a rabid animal results in rabies without pre- or post-exposure prophylaxis, and the disease is nearly always fatal. Nevertheless, a few studies have documented cases of rabies-specific antibodies detection in people with no history of vaccination, suggesting that individuals can be in contact with the virus without developing fatal rabies. To further investigate this possibility of non-lethal human rabies exposure, we carried out a retrospective serological analysis, using both immunoassays (ELISA) and seroneutralization assays (RFFIT), on 430 sera collected between 2005 and 2008 from rural unvaccinated Gabonese populations in the Estuaire and Ogooué-Ivindo provinces. Eleven (11) samples (2.5%) were positive for rabies-specific antibodies using both techniques: 1 in Estuaire and 10 in Ogooué-Ivindo. One of three positive people from the Ogooué-Ivindo province, resampled in early 2023, was still positive for rabies-specific antibodies, suggesting that some degree of immunity can be maintained over many years. Our results also show a marginally significant higher prevalence among hunters. This study demonstrates that rabies circulates actively in Gabon and some unvaccinated individuals living in rural environments can be exposed to the virus and survive, with the development of a significant and specific humoral response that can persist for more than 15 years. This passive seroprevalence survey underlines the need to establish a national surveillance system of rabies in both humans and animals in urban and rural areas, and to enhance access to pre- and post-exposure prophylaxis.

The present study aimed at elucidating the effect of local pH in the extracellular microenvironment of tissue-engineered (TE) constructs on bone cell functions pertinent to new tissue formation. To this aim, we evaluated the osteogenicity process associated with bone constructs prepared from human Bone marrow-derived mesenchymal stem cells (hBMSC) combined with 45S5 bioactive glass (BG), a material that induces alkalinization of the external medium. The pH measured in cell-containing BG constructs was around 8.0, that is, 0.5 U more alkaline than that in two other cell-containing materials (hydroxyapatite/tricalcium phosphate [HA/TCP] and coral) constructs tested. When implanted ectopically in mice, there was no de novo bone tissue in the BG cell-containing constructs, in contrast to results obtained with either HA/TCP or coral ceramics, which consistently promoted the formation of ectopic bone. In addition, the implanted 50:50 composites of both HA/TCP:BG and coral:BG constructs, which displayed a pH of around 7.8, promoted 20–30-fold less amount of bone tissue. Interestingly, hBMSC viability in BG constructs was not affected compared with the other two types of material constructs tested both in vitro and in vivo . Osteogenic differentiation (specifically, the alkaline phosphatase [ALP] activity and gene expression of RUNX2 , ALP , and BSP ) was not affected when hBMSC were maintained in moderate alkaline pH (≤7.90) external milieu in vitro , but was dramatically inhibited at higher pH values. The formation of mineralized nodules in the extracellular matrix of hBMSC was fully inhibited at alkaline (>7.54) pH values. Most importantly, there is a pH range (specifically, 7.9–8.27) at which hBMSC proliferation was not affected, but the osteogenic differentiation of these cells was inhibited. Altogether, these findings provided evidence that excessive alkalinization in the microenvironment of TE constructs (resulting, for example, from material degradation) affects adversely the osteogenic differentiation of osteoprogenitor cells.

The Ebola virus (EBOV) and Marburg virus (MARV) have been in circulation in Africa for several decades and are the cause of numerous outbreaks. There has been very little research on the role of domestic animals in their transmission to humans, but studies have only been conducted in dogs and pigs where relatively high levels of IgG was detected. These levels suggest that ruminants, which have not been studied, should also be investigated. This study aims at evaluating the circulation of MARV and EBOV in dogs, sheep and goats and to assess their exposure to these two viruses. Between November 2018 and March 2023, a total of 448 domestic animal sera or plasma samples, including 128 dogs, 222 goats and 98 sheep, were analyzed by serological and molecular methods. The Luminex technique was employed for the detection of IgG antibodies against EBOV NP, GP, MARV GP and VP40, while EBOV specific and pan-filovirus polymerase chain reaction amplification was used for molecular analysis. All samples tested negative for EBOV and MARV RNA. However, our results showed that 2/128 (1.5%) dogs, 1/222 (0.4%) goats and 3/98 (3.1%) sheep displayed NP and GP anti-EBOV antibodies. In addition, 2/128 (1.5%) dogs displayed GP and VP40 anti-MARV antibodies, while no antibodies were detected in goats and sheep. Over all, these results suggest that dogs and small ruminants are naturally exposed to EBOV and MARV. In the absence of clinically sick individuals, the presence of IgG-positive animals suggests various sources of exposure, such as contaminated fruits with the urine and saliva of bats or dead bats fallen on the ground ate by dogs. These contaminated substrates are both consumed by both dogs and small ruminants. The findings provide new insights into the circulation and exposure of EBOV and MARV in domestic animals, emphasising their potential use as sentinels. Furthermore, they prompt significant considerations regarding the potential risk to humans in this region.

Sickle cell disease (SCD) is a genetic disorder that poses a serious health threat in tropical Africa, which the World Health Organization has declared a public health priority. Its persistence in human populations has been attributed to the resistance it provides toPlasmodium falciparummalaria in its heterozygous state, called sickle cell trait (SCT). Because of migration, SCT is becoming common outside tropical countries: It is now the most important genetic disorder in France, affecting one birth for every 2,400, and one of the most common in the United States. We assess the strength of the association between SCT and malaria, using current data for both SCT and malaria infections. A total of 3,959 blood samples from 195 villages distributed over the entire Republic of Gabon were analyzed. Hemoglobin variants were identified by using HPLCy (HPLC). Infections by three species ofPlasmodiumwere detected by PCR followed by sequencing of a 201-bp fragment of cytochromeb.An increase of 10% inP. falciparummalaria prevalence is associated with an increase by 4.3% of SCT carriers. An increase of 10 y of age is associated with an increase by 5.5% of SCT carriers. Sex is not associated with SCT. These strong associations show that malaria remains a selective factor in current human populations, despite the progress of medicine and the actions undertaken to fight this disease. Our results provide evidence that evolution is still present in humans, although this is sometimes questioned by scientific, political, or religious personalities.

Background/Objectives: Respiratory infections are a major global public health problem, with potentially serious consequences. Indeed, they remain one of the main causes of morbidity and mortality in children under 5 in developing countries. Etiological information on respiratory infections is crucial for prevention and case management strategies. This review describes the etiology of respiratory infections reported in studies conducted in sub-Saharan African countries. Methods: PubMed, HINARI and Google Scholar search engines were used for bibliographic research, and only data from sub-Saharan Africa were considered. Articles published between 2010 and 2023, in English or French, were included in this review. Results: After a thorough search, 2175 documents were identified. Critical review and removal of duplicates identified 347 full-text studies, which underwent rigorous evaluation. A total of 50 articles were retained, with studies conducted in 24 sub-Saharan African countries, most of them in Cameroon (12%). Thirty-three (66%) were cross-sectional studies, and thirty-seven (74%) were hospital-based surveys. Respiratory syncytial virus was most frequently identified (0.6% to 59%), followed by rhinovirus (7.5% to 73%). The most frequent bacteria were Streptococcus pneumoniae (1–96%) and Haemophilus influenzae (2.5–54%). Conclusions: This study suggests that acute respiratory infections in sub-Saharan Africa, mainly in children, are primarily caused by viruses and a few bacteria.

An association between malaria and risk for death among patients with Ebola virus disease has suggested within-host interactions between Plasmodium falciparum parasites and Ebola virus. To determine whether such an interaction might also influence the probability of acquiring either infection, we used a large snapshot surveillance study from rural Gabon to test if past exposure to Ebola virus is associated with current infection with Plasmodium spp. during nonepidemic conditions. We found a strong positive association, on population and individual levels, between seropositivity for antibodies against Ebola virus and the presence of Plasmodium parasites in the blood. According to a multiple regression model accounting for other key variables, antibodies against Ebola virus emerged as the strongest individual-level risk factor for acquiring malaria. Our results suggest that within-host interactions between malaria parasites and Ebola virus may underlie epidemiologic associations.

Ebola virus (EBOV) is a highly virulent human pathogen. Recovery of infected patients is associated with efficient EBOV-specific immunoglobulin G (IgG) responses, whereas fatal outcome is associated with defective humoral immunity. As B-cell epitopes on EBOV are poorly defined, we sought to identify specific epitopes in four EBOV proteins (Glycoprotein (GP), Nucleoprotein (NP), and matrix Viral Protein (VP)40 and VP35). For the first time, we tested EBOV IgG+ sera from asymptomatic individuals and symptomatic Gabonese survivors, collected during the early humoral response (seven days after the end of symptoms) and the late memory phase (7-12 years post-infection). We also tested sera from EBOV-seropositive patients who had never had clinical signs of hemorrhagic fever or who lived in non-epidemic areas (asymptomatic subjects). We found that serum from asymptomatic individuals was more strongly reactive to VP40 peptides than to GP, NP or VP35. Interestingly, anti-EBOV IgG from asymptomatic patients targeted three immunodominant regions of VP40 reported to play a crucial role in virus assembly and budding. In contrast, serum from most survivors of the three outbreaks, collected a few days after the end of symptoms, reacted mainly with GP peptides. However, in asymptomatic subjects the longest immunodominant domains were identified in GP, and analysis of the GP crystal structure revealed that these domains covered a larger surface area of the chalice bowl formed by three GP1 subunits. The B-cell epitopes we identified in the EBOV VP35, VP40, NP and GP proteins may represent important tools for understanding the humoral response to this virus and for developing new antibody-based therapeutics or detection methods.