Severe acute respiratory syndrome coronavirus (SARS-CoV)-2 and its associated pathology, COVID-19, have been of particular concerns these last months due to the worldwide burden they represent. The number of cases requiring intensive care being the critical point in this epidemic, a better understanding of the pathophysiology leading to these severe cases is urgently needed. Tissue lesions can be caused by the pathogen or can be driven by an overwhelmed immune response. Focusing on SARS-CoV-2, we and others have observed that this virus can trigger indeed an immune response that can be dysregulated in severe patients and leading to further injury to multiple organs. The purpose of the review is to bring to light the current knowledge about SARS-CoV-2 virologic and immunologic features. Thus, we address virus biology, life cycle, tropism for many organs and how ultimately it will affect several host biological and physiological functions, notably the immune response. Given that therapeutic avenues are now highly warranted, we also discuss the immunotherapies available to manage the infection and the clinical outcomes.

The treatment of sepsis and septic shock remains a major public health issue due to the associated morbidity and mortality. Despite an improvement in the understanding of the physiological and pathological mechanisms underlying its genesis and a growing number of studies exploring an even higher range of targeted therapies, no significant clinical progress has emerged in the past decade. In this context, mesenchymal stem cells (MSCs) appear more and more as an attractive approach for cell therapy both in experimental and clinical models. Pre-clinical data suggest a cornerstone role of these cells and their secretome in the control of the host immune response. Host-derived factors released from infected cells (i.e., alarmins, HMGB1, ATP, DNA) as well as pathogen-associated molecular patterns (e.g., LPS, peptidoglycans) can activate MSCs located in the parenchyma and around vessels to upregulate the expression of cytokines/chemokines and growth factors that influence, respectively, immune cell recruitment and stem cell mobilization. However, the way in which MSCs exert their beneficial effects in terms of survival and control of inflammation in septic states remains unclear. This review presents the interactions identified between MSCs and mediators of immunity and tissue repair in sepsis. We also propose paradigms related to the plausible roles of MSCs in the process of sepsis and septic shock. Finally, we offer a presentation of experimental and clinical studies and open the way to innovative avenues of research involving MSCs from a prognostic, diagnostic, and therapeutic point of view in sepsis.

Mesenchymal stem cells (MSCs) play a critical role in response to stress such as infection. They initiate the removal of cell debris, exert major immunoregulatory activities, control pathogens, and lead to a remodeling/scarring phase. Thus, host-derived ‘danger’ factors released from damaged/infected cells (called alarmins, e.g., HMGB1, ATP, DNA) as well as pathogen-associated molecular patterns (LPS, single strand RNA) can activate MSCs located in the parenchyma and around vessels to upregulate the expression of growth factors and chemoattractant molecules that influence immune cell recruitment and stem cell mobilization. MSC, in an ultimate contribution to tissue repair, may also directly trans- or de-differentiate into specific cellular phenotypes such as osteoblasts, chondrocytes, lipofibroblasts, myofibroblasts, Schwann cells, and they may somehow recapitulate their neural crest embryonic origin. Failure to terminate such repair processes induces pathological scarring, termed fibrosis, or vascular calcification. Interestingly, many viruses and particularly those associated to chronic infection and inflammation may hijack and polarize MSC’s immune regulatory activities. Several reports argue that MSC may constitute immune privileged sanctuaries for viruses and contributing to long-lasting effects posing infectious challenges, such as viruses rebounding in immunocompromised patients or following regenerative medicine therapies using MSC. We will herein review the capacity of several viruses not only to infect but also to polarize directly or indirectly the functions of MSC (immunoregulation, differentiation potential, and tissue repair) in clinical settings.

The complement (C) innate immune system has been shown to be activated in the tumor microenvironment of various cancers. The C may support tumor growth by modulating the immune response and promoting angiogenesis through the actions of C anaphylatoxins (e.g., C5a, C3a). The C has important double-edged sword functions in the brain, but little is known about its role in brain tumors. Hence, we analyzed the distribution and the regulated expression of C3a and its receptor C3aR in various primary and secondary brain tumors. We found that C3aR was dramatically upregulated in Grade 4 diffuse gliomas, i.e., glioblastoma multiforme, IDH-wildtype (GBM) and astrocytoma, IDH-mutant, Grade 4, and was much less expressed in other brain tumors. C3aR was observed in tumor-associated macrophages (TAM) expressing CD68, CD18, CD163, and the proangiogenic VEGF. Robust levels of C3a were detected in the parenchyma of GBM as a possible result of Bb-dependent C activation of the alternative C pathway. Interestingly, in vitro models identified TGF-β1 as one of the most potent growth factors that upregulate VEGF, C3, and C3aR in TAM (PMA-differentiated THP1) cell lines. Further studies should help to delineate the functions of C3a/C3aR on TAMs that promote chemotaxis/angiogenesis in gliomas and to explore the therapeutic applications of C3aR antagonists for brain tumors.

Glioblastoma, IDH wild-type is the most common and aggressive form of glial tumors. The exact mechanisms of glioblastoma oncogenesis, including the identification of the glioma-initiating cell, are yet to be discovered. Recent studies have led to the hypothesis that glioblastoma arises from neural stem cells and glial precursor cells and that cell lineage constitutes a key determinant of the glioblastoma molecular subtype. These findings brought significant advancement to the comprehension of gliomagenesis. However, the cellular origin of glioblastoma with mesenchymal molecular features remains elusive. Mesenchymal stromal cells emerge as potential glioblastoma-initiating cells, especially with regard to the mesenchymal molecular subtype. These fibroblast-like cells, which derive from the neural crest and reside in the perivascular niche, may underlie gliomagenesis and exert pro-tumoral effects within the tumor microenvironment. This review synthesizes the potential roles of mesenchymal stromal cells in the context of glioblastoma and provides novel research avenues to better understand this lethal disease.