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1.
Emerg Microbes Infect ; 10(1): 2151-2168, 2021 Dec.
Article in English | MEDLINE | ID: covidwho-1541485

ABSTRACT

Infection by (re-)emerging RNA arboviruses including Chikungunya virus (CHIKV) and Mayaro virus primarily cause acute febrile disease and transient polyarthralgia. However, in a significant subset of infected individuals, debilitating arthralgia persists for weeks over months up to years. The underlying immunopathogenesis of chronification of arthralgia upon primary RNA-viral infection remains unclear. Here, we analysed cell-intrinsic responses to ex vivo arthritogenic alphaviral infection of primary human synovial fibroblasts isolated from knee joints, one the most affected joint types during acute and chronic CHIKV disease. Synovial fibroblasts were susceptible and permissive to alphaviral infection. Base-line and exogenously added type I interferon (IFN) partially and potently restricted infection, respectively. RNA-seq revealed a CHIKV infection-induced transcriptional profile that comprised upregulation of expression of several hundred IFN-stimulated and arthralgia-mediating genes. Single-cell virus-inclusive RNA-seq uncovered a fine-tuned switch from induction to repression of cell-intrinsic immune responses depending on the abundance of viral RNA in an individual cell. Specifically, responses were most pronounced in cells displaying low-to-intermediate amounts of viral RNA and absence of virus-encoded, fluorescent reporter protein expression, arguing for efficient counteraction of innate immunity in cells expressing viral antagonists at sufficient quantities. In summary, cell-intrinsic sensing of viral RNA that potentially persists or replicates at low levels in synovial fibroblasts and other target cell types in vivo may contribute to the chronic arthralgia induced by alphaviral infections. Our findings might advance our understanding of the immunopathophysiology of long-term pathogenesis of RNA-viral infections.


Subject(s)
Arbovirus Infections/virology , Arboviruses/physiology , Arthralgia/virology , Immunity, Innate , RNA, Viral/genetics , Synovial Fluid/immunology , Arbovirus Infections/genetics , Arbovirus Infections/immunology , Arboviruses/genetics , Arthralgia/genetics , Arthralgia/immunology , Cells, Cultured , Fibroblasts/immunology , Fibroblasts/virology , Humans , RNA, Viral/metabolism , Single-Cell Analysis , Synovial Fluid/cytology , Virus Replication
2.
Immunology ; 163(3): 239-249, 2021 07.
Article in English | MEDLINE | ID: covidwho-1434725

ABSTRACT

Communication between stromal and immune cells is essential to maintain tissue homeostasis, mount an effective immune response and promote tissue repair. This 'crosstalk' occurs in both the steady state and following a variety of insults, for example, in response to local injury, at sites of infection or cancer. What do we mean by crosstalk between cells? Reciprocal activation and/or regulation occurs between immune and stromal cells, by direct cell contact and indirect mechanisms, including the release of soluble cytokines. Moving beyond cell-to-cell contact, this review investigates the complexity of 'cross-space' cellular communication. We highlight different examples of cellular communication by a variety of lung stromal and immune cells following tissue insults. This review examines how the 'geography of the lung microenvironment' is altered in various disease states; more specifically, we investigate how this influences lung epithelial cells and fibroblasts via their communication with immune cells and each other.


Subject(s)
CD8-Positive T-Lymphocytes/immunology , Epithelial Cells/immunology , Fibroblasts/immunology , Lung/pathology , Stromal Cells/immunology , Animals , Cell Communication , Cellular Microenvironment , Humans , Immunity, Cellular
3.
Commun Biol ; 4(1): 631, 2021 05 27.
Article in English | MEDLINE | ID: covidwho-1283664

ABSTRACT

IL22 is an important cytokine involved in the intestinal defense mechanisms against microbiome. By using ileum-derived organoids, we show that the expression of anti-microbial peptides (AMPs) and anti-viral peptides (AVPs) can be induced by IL22. In addition, we identified a bacterial and a viral route, both leading to IL22 production by T cells, but via different pathways. Bacterial products, such as LPS, induce enterocyte-secreted SAA1, which triggers the secretion of IL6 in fibroblasts, and subsequently IL22 in T cells. This IL22 induction can then be enhanced by macrophage-derived TNFα in two ways: by enhancing the responsiveness of T cells to IL6 and by increasing the expression of IL6 by fibroblasts. Viral infections of intestinal cells induce IFNß1 and subsequently IL7. IFNß1 can induce the expression of IL6 in fibroblasts and the combined activity of IL6 and IL7 can then induce IL22 expression in T cells. We also show that IL22 reduces the expression of viral entry receptors (e.g. ACE2, TMPRSS2, DPP4, CD46 and TNFRSF14), increases the expression of anti-viral proteins (e.g. RSAD2, AOS, ISG20 and Mx1) and, consequently, reduces the viral infection of neighboring cells. Overall, our data indicates that IL22 contributes to the innate responses against both bacteria and viruses.


Subject(s)
Interleukins/biosynthesis , Interleukins/metabolism , Animals , Anti-Bacterial Agents/metabolism , Antiviral Agents/metabolism , Cell Culture Techniques , Cytokines/immunology , Cytokines/metabolism , Disease Models, Animal , Enterocytes/immunology , Enterocytes/metabolism , Female , Fibroblasts/immunology , Fibroblasts/metabolism , Interleukins/immunology , Intestinal Mucosa/metabolism , Intestines/physiology , Mice , Mice, Inbred C57BL , Myeloid Cells/immunology , Myeloid Cells/metabolism , Organoids/metabolism , Pore Forming Cytotoxic Proteins/genetics , Pore Forming Cytotoxic Proteins/metabolism
4.
Mol Med ; 26(1): 95, 2020 10 14.
Article in English | MEDLINE | ID: covidwho-873932

ABSTRACT

Pulmonary fibrosis arises from the repeated epithelial mild injuries and insufficient repair lead to over activation of fibroblasts and excessive deposition of extracellular matrix, which result in a mechanical stretched niche. However, increasing mechanical stress likely exists before the establishment of fibrosis since early micro injuries increase local vascular permeability and prompt cytoskeletal remodeling which alter cellular mechanical forces. It is noteworthy that COVID-19 patients with severe hypoxemia will receive mechanical ventilation as supportive treatment and subsequent pathology studies indicate lung fibrosis pattern. At advanced stages, mechanical stress originates mainly from the stiff matrix since boundaries between stiff and compliant parts of the tissue could generate mechanical stress. Therefore, mechanical stress has a significant role in the whole development process of pulmonary fibrosis. The alveoli are covered by abundant capillaries and function as the main gas exchange unit. Constantly subject to variety of damages, the alveolar epithelium injuries were recently recognized to play a vital role in the onset and development of idiopathic pulmonary fibrosis. In this review, we summarize the literature regarding the effects of mechanical stress on the fundamental cells constituting the alveoli in the process of pulmonary fibrosis, particularly on epithelial cells, capillary endothelial cells, fibroblasts, mast cells, macrophages and stem cells. Finally, we briefly review this issue from a more comprehensive perspective: the metabolic and epigenetic regulation.


Subject(s)
Coronavirus Infections/immunology , Epigenesis, Genetic/immunology , Idiopathic Pulmonary Fibrosis/immunology , Mechanotransduction, Cellular/immunology , Pneumonia, Viral/immunology , Pulmonary Embolism/immunology , Respiratory Insufficiency/immunology , Alveolar Epithelial Cells/immunology , Alveolar Epithelial Cells/pathology , Betacoronavirus/immunology , Betacoronavirus/pathogenicity , Biomechanical Phenomena , COVID-19 , Coronavirus Infections/genetics , Coronavirus Infections/pathology , Coronavirus Infections/virology , Cytokines/genetics , Cytokines/immunology , Endothelial Cells/immunology , Endothelial Cells/pathology , Fibroblasts/immunology , Fibroblasts/pathology , Humans , Idiopathic Pulmonary Fibrosis/genetics , Idiopathic Pulmonary Fibrosis/pathology , Idiopathic Pulmonary Fibrosis/virology , Lung/blood supply , Lung/immunology , Lung/pathology , Macrophages/immunology , Macrophages/pathology , Mechanotransduction, Cellular/genetics , Pandemics , Pneumonia, Viral/genetics , Pneumonia, Viral/pathology , Pneumonia, Viral/virology , Pulmonary Embolism/genetics , Pulmonary Embolism/pathology , Pulmonary Embolism/virology , Respiratory Insufficiency/genetics , Respiratory Insufficiency/pathology , Respiratory Insufficiency/virology , SARS-CoV-2 , Stress, Mechanical
5.
Viral Immunol ; 33(6): 468-476, 2020.
Article in English | MEDLINE | ID: covidwho-94792

ABSTRACT

As a zoonotic disease, ovine contagious pustular dermatitis (Orf) is a serious threat to sheep as well as humans. Orf virus (ORFV) interferon resistance protein (VIR) is the principal virulence protein that encodes a dsRNA-binding protein to inhibit host antiviral response. p53 is one of the key proteins of the host antiviral innate immunity. It not only enhances type I interferon secretion but also induces apoptosis in infected cells, and plays a crucial role in the immune response against various viral infections. However, it remains to be elucidated what role p53 plays in ORFV replication and whether ORFV's own protein VIR regulates p53 expression to promote self-replication. In this study, we showed that p53 has an antiviral effect on ORFV and can inhibit ORFV replication. In addition, ORFV nonstructural protein VIR interacts with p53 and degrades p53, which inhibits p53-mediated positive regulation of downstream antiviral genes. This study provides new insight into the immune evasion mediated by ORFV and identifies VIR as an antagonistic factor for ORFV to evade the antiviral response.


Subject(s)
Host Microbial Interactions/genetics , Orf virus/genetics , Tumor Suppressor Protein p53/genetics , Viral Proteins/genetics , Virus Replication/genetics , Animals , Cell Line , Cricetinae , Ecthyma, Contagious/virology , Fibroblasts/immunology , Fibroblasts/virology , Gene Expression Regulation, Viral , Goats , Immune Evasion/genetics , Immunity, Innate , Kidney/cytology , Orf virus/physiology , Sheep , Skin/cytology , Viral Proteins/metabolism
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