RESUMO
NKT cells are innate-like T cells, recruited to the skin during viral infection, yet their contributions to long-term immune memory to viruses are unclear. We identified granzyme K, a product made by cytotoxic cells including NKT cells, is linked to induction of Th1-associated antibodies during primary dengue virus (DENV) infection in humans. We examined the role of NKT cells in vivo using DENV-infected mice lacking CD1d-dependent (CD1ddep) NKT cells. In CD1d-KO mice, Th1-polarized immunity and infection resolution were impaired, which was dependent on intrinsic NKT cell production of IFN-γ, since it was restored by adoptive transfer of WT but not IFN-γ-KO NKT cells. Furthermore, NKT cell deficiency triggered immune bias, resulting in higher levels of Th2-associated IgG1 than Th1-associated IgG2a, which failed to protect against a homologous DENV re-challenge and promoted antibody-dependent enhanced disease during secondary heterologous infections. Similarly, Th2-immunity, typified by a higher IgG4:IgG3 ratio, was associated with worsened human disease severity during secondary infections. Thus, CD1ddep NKT cells establish Th1 polarity during the early innate response to DENV, which promotes infection resolution, memory formation and long-term protection from secondary homologous and heterologous infections. These observations illustrate how early innate immune responses during primary infections can influence secondary infection outcomes.
RESUMO
Lung inflammation is a hallmark of Coronavirus disease 2019 (COVID-19) in patients who are severely ill, and the pathophysiology of disease is thought to be immune mediated. Mast cells (MCs) are polyfunctional immune cells present in the airways, where they respond to certain viruses and allergens and often promote inflammation. We observed widespread degranulation of MCs during acute and unresolved airway inflammation in SARS-CoV-2-infected mice and nonhuman primates. Using a mouse model of MC deficiency, MC-dependent interstitial pneumonitis, hemorrhaging, and edema in the lung were observed during SARS-CoV-2 infection. In humans, transcriptional changes in patients requiring oxygen supplementation also implicated cells with a MC phenotype in severe disease. MC activation in humans was confirmed through detection of MC-specific proteases, including chymase, the levels of which were significantly correlated with disease severity and with biomarkers of vascular dysregulation. These results support the involvement of MCs in lung tissue damage during SARS-CoV-2 infection in animal models and the association of MC activation with severe COVID-19 in humans, suggesting potential strategies for intervention.
Assuntos
COVID-19 , Humanos , Animais , COVID-19/patologia , Mastócitos/patologia , SARS-CoV-2 , Pulmão/patologia , Inflamação/patologiaRESUMO
Dengue virus infects several million people each year. Although usually a self-limiting disease, some patients can develop life-threatening severe complications, characterized by plasma leakage, hemorrhaging, and shock. The signs and symptoms of severe disease usually arise late in the disease course when patients are recovering and fever has subsided, making it difficult to predict. Efforts are underway to identify risk factors and biomarkers that can accurately predict disease severity in the acute febrile phase of the disease, facilitating early intervention and treatment strategies for those at greatest risk. In this review we discuss recent advancements in identifying risk factors and biomarkers for the prognosis of severe dengue.
Assuntos
Vírus da Dengue/fisiologia , Dengue Grave/sangue , Dengue Grave/virologia , Animais , Biomarcadores/sangue , Vírus da Dengue/genética , Humanos , Prognóstico , Fatores de Risco , Dengue Grave/diagnóstico , Dengue Grave/epidemiologia , Índice de Gravidade de DoençaRESUMO
Mast cells (MCs) are long-lived immune cells. They are armed with preformed mediators within granules that can be instantaneously released in response to an invading pathogen, including certain viruses. At the skin and mucosae, they initiate innate immune responses and promote the development of adaptive immune responses, through cellular recruitment or antigen presentation. However, systemic MC activation may promote immune pathologies through their vasoactive proteases and biogenic amines. Recently, MC products were identified to contribute to pathologies associated with viral hemorrhagic fever, such vascular leakage and thrombocytopenia. Similar associations of MCs with disease severity have been noted for certain respiratory viral pathogens. Here we discuss the specific MC responses to viruses and their influences on functional immune outcomes during infection.
Assuntos
Imunidade Inata/imunologia , Mastócitos/imunologia , Viroses/imunologia , Animais , HumanosRESUMO
Dengue virus (DENV) infection causes a characteristic pathology in humans involving dysregulation of the vascular system. In some patients with dengue hemorrhagic fever (DHF), vascular pathology can become severe, resulting in extensive microvascular permeability and plasma leakage into tissues and organs. Mast cells (MCs), which line blood vessels and regulate vascular function, are able to detect DENV in vivo and promote vascular leakage. Here, we identified that a MC-derived protease, tryptase, is consequential for promoting vascular permeability during DENV infection, through inducing breakdown of endothelial cell tight junctions. Injected tryptase alone was sufficient to induce plasma loss from the circulation and hypovolemic shock in animals. A potent tryptase inhibitor, nafamostat mesylate, blocked DENV-induced vascular leakage in vivo. Importantly, in two independent human dengue cohorts, tryptase levels correlated with the grade of DHF severity. This study defines an immune mechanism by which DENV can induce vascular pathology and shock.