Our results highlight the differential in vitro pathogenesis of respiratory viruses during the acute infection phase and their ability to persist under immune tolerance. These data help to appreciate the range of disease severity observed in vivo and the occurrence of chronic respiratory tract infections in immunocompromised hosts.

Rhinoviruses (RVs) and respiratory enteroviruses (EVs) are leading causes of upper respiratory tract infections and among the most frequent infectious agents in humans worldwide. Both are classified in the Enterovirus genus within the Picornaviridae family and they have been assigned to seven distinct species, RV-A, B, C and EV-A, B, C, D. As viral infections of public health significance, they represent an important financial burden on health systems worldwide. However, the lack of efficient antiviral treatment or vaccines against these highly prevalent pathogens prevents an effective management of RV-related diseases. Current advances in molecular diagnostic techniques have revealed the presence of RV in the lower respiratory tract and its role in lower airway diseases is increasingly reported. In addition to an established etiological role in the common cold, these viruses demonstrate an unexpected capacity to spread to other body sites under certain conditions. Some of these viruses have received particular attention recently, such as EV-D68 that caused a large outbreak of respiratory illness in 2014, respiratory EVs from species C, or viruses within the newly-discovered RV-C species. This review provides an update of the latest findings on clinical and fundamental aspects of RV and respiratory EV, including a summary of basic knowledge of their biology.

The intestinal epithelial layer serves as a physical and functional barrier between the microbiota in the lumen and immunologically active submucosa. Th17 T-cell function protects the gut epithelium from aggression from microbes and their by-products. Loss of barrier function has been associated with enhanced translocation of microbial products which act as endotoxins, leading to local and systemic immune activation. Whereas the inflammatory role of LPS produced by Gram-negative bacteria has been extensively studied, the role of fungal products such as β-D-glucan remains only partially understood. As HIV infection is characterized by impaired gut Th17 function and increased gut permeability, we critically review mechanisms of immune activation related to fungal translocation in this viral infection. Additionally, we discuss markers of fungal translocation for diagnosis and monitoring of experimental treatment responses. Targeting gut barrier dysfunction and reducing fungal translocation are emerging strategies for the prevention and treatment of HIV-associated inflammation and may prove useful in other inflammatory chronic diseases.

Despite their genetic similarities, enteric and respiratory enteroviruses (EVs) have highly heterogeneous biophysical properties and cause a vast diversity of human pathologies. In vitro differences include acid sensitivity, optimal growth temperature and tissue tropism, which reflect a preferential in vivo replication in the respiratory or gastrointestinal tract and are thus key determinants of EV virulence. To investigate the underlying cause of these differences, we generated chimeras at the capsid-level between EV-D68 (a respiratory EV) and EV-D94 (an enteric EV). Although some chimeras were nonfunctional, EV-D94 with both the capsid and 2A protease or the capsid only of EV-D68 were both viable. Using this latter construct, we performed several functional assays, which indicated that capsid proteins determine acid sensitivity and tropism in cell lines and in respiratory, intestinal and neural tissues. Additionally, capsid genes were shown to also participate in determining the optimal growth temperature, since EV-D94 temperature adaptation relied on single mutations in VP1, while constructs with EV-D68 capsid could not adapt to higher temperatures. Finally, we demonstrate that EV-D68 maintains residual binding-capacity after acid-treatment despite a loss of infectivity. In contrast, non-structural rather than capsid proteins modulate the innate immune response in tissues. These unique biophysical insights expose another layer in the phenotypic diversity of one of world’s most prevalent pathogens and could aid target selection for vaccine or antiviral development.

Growth differentiation factor 15 (GDF-15) is a transforming growth factor (TGF)-β superfamily cytokine that plays a central role in metabolism regulation. Produced in response to mitochondrial stress, tissue damage or hypoxia, this cytokine has emerged as one of the strongest predictors of disease severity during inflammatory conditions, cancers and infections. Reports suggest that GDF-15 plays a tissue protective role via sympathetic and metabolic adaptation in the context of mitochondrial damage, although the exact mechanisms involved remain uncertain. In this review, we discuss the emergence of GDF-15 as a distinctive marker of viral infection severity, especially in the context of COVID-19. We will critically review the role of GDF-15 as an inflammation-induced mediator of disease tolerance, through metabolic and immune reprogramming. Finally, we discuss potential mechanisms of GDF-15 elevation during COVID-19 cytokine storm and its limitations. Altogether, this cytokine seems to be involved in disease tolerance to viral infections including SARS-CoV-2, paving the way for novel therapeutic interventions.