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The passing of Professor Philippe Gasque on 11 July 2024 marked the loss of a prominent figure in immunology and infectious disease research [...].The passing of Professor Philippe Gasque on 11 July 2024 marked the loss of a prominent figure in immunology and infectious disease research [...].

Extracellular vesicles (EVs), produced during viral infections, are of emerging interest in understanding infectious processes and host–pathogen interactions. EVs and exosomes in particular have the natural ability to transport nucleic acids, proteins, and other components of cellular or viral origin. Thus, they participate in intercellular communication, immune responses, and infectious and pathophysiological processes. Some viruses are known to hijack the cell production and content of EVs for their benefit. Here, we investigate whether two pathogenic flaviviruses i.e., Zika Virus (ZIKV) and Dengue virus (DENV2) could have an impact on the features of EVs. The analysis of EVs produced by infected cells allowed us to identify that the non-structural protein 1 (NS1), described as a viral toxin, is associated with exosomes. This observation could be confirmed under conditions of overexpression of recombinant NS1 from each flavivirus. Using different isolation methods (i.e., exosome isolation kit, size exclusion chromatography, Polyethylene Glycol enrichment, and ELISA capture), we showed that NS1 was present as a dimer at the surface of excreted exosomes, and that this association could occur in the extracellular compartment. This finding could be of major importance in a physiological context. Indeed, this capacity of NS1 to address EVs and its implication in the pathophysiology during Dengue or Zika diseases should be explored. Furthermore, exosomes that have demonstrated a natural capacity to vectorize NS1 could serve as useful tools for vaccine development.

To characterize the immunity developed by patients infected by chikungunya virus (CHIKV), we studied the intensity and specificity of CHIKV-specific T cells mediated responses in chronic and recovered patients at 12 to 24 months post-infection. T cells were challenged in vitro against CHIKV synthetic peptides covering the length of three viral proteins, capsid, E2 and nsP1 proteins as well as all inactivated virus particles. Cytokine production was assessed by ELISPOT and intracellular labeling. T cells producing IFN-γ were detected against CHIKV in 85% patient's cells either by direct ELISPOT assay (69% of patients) or after expansion of memory T cells allowing the detection of both CD4 and CD8 specific-T cells in 16% additional cases. The IFN-γ response was mainly engaged in response to nsP1 or E2 (52% and 46% cases, respectively) but in only 27% cases against the capsid. The anti-E2 response represented half the magnitude of the total CHIKV IFN-γ production and was mainly directed against the C-terminal half part of the protein. Almost all patients had conserved a T cell specific response against CHIKV with a clear hierarchy of T cell responses (CD8 > CD4) engaged against E2 > nsP1 > capsid. More importantly, the intensity of responses was not significantly different between recovered and chronic patients. These findings constitute key elements to a better understanding of patient T cell immunoreactivity against CHIKV and argue against a possible defect of T cell immunoresponse in the chronicity post-CHIKV infection.

Background Chikungunya Virus (ChikV) surprised by a massive re-emerging outbreak in Indian Ocean in 2006, reaching Europe in 2007 and exhibited exceptional severe physiopathology in infants and elderly patients. In this context, it is important to analyze the innate immune host responses triggered against ChikV. Autophagy has been shown to be an important component of the innate immune response and is involved in host defense elimination of different pathogens. However, the autophagic process was recently observed to be hijacked by virus for their own replication. Here we provide the first evidence that hallmarks of autophagy are specifically found in HEK.293 infected cells and are involved in ChikV replication. Methods To test the capacity of ChikV to mobilize the autophagic machinery, we performed fluorescence microscopy experiments on HEK.GFP.LC3 stable cells, and followed the LC3 distribution during the time course of ChikV infection. To confirm this, we performed electron microscopy on HEK.293 infected cells. To test the effect of ChikV-induced-autophagy on viral replication, we blocked the autophagic process, either by pharmacological (3-MA) or genetic inhibition (siRNA against the transcript of Beclin 1, an autophagic protein), and analyzed the percentage of infected cells and the viral RNA load released in the supernatant. Moreover, the effect of induction of autophagy by Rapamycin on viral replication was tested. Results The increasing number of GFP-LC3 positive cells with a punctate staining together with the enhanced number of GFP-LC3 dots per cell showed that ChikV triggered an autophagic process in HEK.293 infected cells. Those results were confirmed by electron microscopy analysis since numerous membrane-bound vacuoles characteristic of autophagosomes were observed in infected cells. Moreover, we found that inhibition of autophagy, either by biochemical reagent and RNA interference, dramatically decreases ChikV replication. Conclusions Taken together, our results suggest that autophagy may play a promoting role in ChikV replication. Investigating in details the relationship between autophagy and viral replication will greatly improve our knowledge of the pathogenesis of ChikV and provide insight for the design of candidate antiviral therapeutics.

The mosquito-borne viral disease dengue is a global public health problem causing a wide spectrum of clinical manifestations ranging from mild dengue fever to severe dengue with plasma leakage and bleeding which are often fatal. To date, there are no specific medications to treat dengue and prevent the risk of hemorrhage. Dengue is caused by one of four genetically related but antigenically distinct serotypes DENV-1–DENV-4. The growing burden of the four DENV serotypes has intensified both basic and applied research to better understand dengue physiopathology. Research has shown that the secreted soluble hexameric form of DENV nonstructural protein-1 (sNS1) plays a significant role in the pathogenesis of severe dengue. Here, we provide an overview of the current knowledge about the role of sNS1 in the immunopathogenesis of dengue disease. We discuss the potential use of sNS1 in future vaccine development and its potential to improve dengue vaccine efficiency, particularly against severe dengue illness.

The neurological complications of infection by the mosquito-borne Zika virus (ZIKV) include Guillain–Barré syndrome (GBS), an acute inflammatory demyelinating polyneuritis. GBS was first associated with recent ZIKV epidemics caused by the emergence of the ZIKV Asian lineage in South Pacific. Here, we hypothesize that ZIKV-associated GBS relates to a molecular mimicry between viral envelope E (E) protein and neural proteins involved in GBS. The analysis of the ZIKV epidemic strains showed that the glycan loop (GL) region of the E protein includes an IVNDT motif which is conserved in voltage-dependent L-type calcium channel subunit alpha-1C (Cav1.2) and Heat Shock 70 kDa protein 12A (HSP70 12A). Both VSCC-alpha 1C and HSP70 12A belong to protein families which have been associated with neurological autoimmune diseases in central nervous system. The purpose of our in silico analysis is to point out that IVNDT motif of ZIKV E-GL region should be taken in consideration for the development of safe and effective anti-Zika vaccines by precluding the possibility of adverse neurologic events including autoimmune diseases such as GBS through a potent mimicry with Heat Shock 70 kDa protein 12A (HSP70 12A).

The human genome is densely populated with transposons and transposon-like repetitive elements. Although the impact of these transposons and elements on human genome evolution is recognized, the significance of subtle variations in their sequence remains mostly unexplored. Here we report homozygosity mapping of an infantile neurodegenerative disease locus in a genetic isolate. Complete DNA sequencing of the 400-kb linkage locus revealed a point mutation in a primate-specific retrotransposon that was transcribed as part of a unique noncoding RNA, which was expressed in the brain. In vitro knockdown of this RNA increased neuronal apoptosis, consistent with the inappropriate dosage of this RNA in vivo and with the phenotype. Moreover, structural analysis of the sequence revealed a small RNA-like hairpin that was consistent with the putative gain of a functional site when mutated. We show here that a mutation in a unique transposable element-containing RNA is associated with lethal encephalopathy, and we suggest that RNAs that harbor evolutionarily recent repetitive elements may play important roles in human brain development.

Background Infection with Chikungunya alphavirus (CHIKV) can cause severe arthralgia and chronic arthritis in humans with persistence of the virus in perivascular macrophages of the synovial membrane by mechanisms largely ill-characterized. Findings We herein analysed the innate immune response (cytokine and programmed cell death) of RAW264.7 mouse macrophages following CHIKV infection. We found that the infection was restrained to a small percentage of cells and was not associated with a robust type I IFN innate immune response (IFN-α4 and ISG56). TNF-α, IL-6 and GM-CSF expression were upregulated while IFN-γ, IL-1α, IL-2, IL-4, IL-5, IL-10 or IL-17 expression could not be evidenced prior to and after CHIKV exposure. Although CHIKV is known to drive apoptosis in many cell types, we found no canonical signs of programmed cell death (cleaved caspase-3, -9) in infected RAW264.7 cells. Conclusion These data argue for the capacity of CHIKV to infect and drive a specific innate immune response in RAW264.7 macrophage cell which seems to be polarized to assist viral persistence through the control of apoptosis and IFN signalling.

Major epidemics of Chikungunya have re-emerged with millions of cases worldwide. What was once largely a tropical disease in poorer countries is now recognized as a major global health issue. The disease is perpetuated by the alphavirus Chikungunya, and is transmitted by Aedes mosquitoes. The infection is highly symptomatic, with fever, skin rash and incapacitating arthralgia, which can evolve to chronic arthritis and rheumatism in elderly patients. Mother-to-child transmission, encephalitis, Guillain-Barré syndrome and deaths have been noted. In this article, we will highlight the epidemiological, clinical, virological and immunological aspects of the disease and mention the therapies that have been used during recent epidemics. Novel prevention measures to control the mosquito and a new vaccine are highly warranted.

Adipose tissue contains a stroma that can be easily isolated. Thus, human adipose tissue presents an source of multipotent stromal cells. In order to determine the implication of hematopoietic markers in adipocyte biology, we have defined part of the phenotype of the human adipose tissue-derived stromal cells, and compared this to fully differentiated adipocytes. Flow cytometry demonstrates that the protein expression phenotype of both cell types are similar and includes the expression of CD10, CD13, CD34, CD36, CD55, CD59 and CD65. No significant difference between subcutaneous and omental adipose tissue could be demonstrated concerning the expression of these markers. However, the expression of CD34, CD36 and CD65 is cell-dependent. While the expression of CD36 and CD65 doubled between stromal cells and mature adipocytes, the expression of CD34 decreased, despite this protein being present on the mature adipocyte. As CD34 is described as a stem cell marker and it being unlikely to be expressed on differentiated cells, this result was confirmed by immunostaining and western blot. The clear function of this protein on the adipocyte membrane remains to be determined. The characterization of new proteins on mature adipocytes could have broad implications for the comprehension of the biology of this tissue.