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Controlled infection with SARS-CoV-2 of people who hadn’t previously been exposed to the virus reveals how molecular and cellular signatures of the immune response portend effective defence against COVID-19.Controlled human infection with SARS-CoV-2 to track defence responses. [ABSTRACT FROM AUTHOR]

Understanding what contributes to the development of severe COVID-19 would be of great clinical benefit. Analysis of people in whom this occurred pinpoints a key role for the signalling pathway mediated by type I interferon proteins. Genetic and antibody clues to a cause of life-threatening illness., Author(s): Eric Meffre, Akiko Iwasaki Author Affiliations: Interferon deficiency can lead to severe COVID Infection with the SARS-CoV-2 coronavirus results in diverse outcomes for COVID-19, with the disease tending to [...]

Interferon-[gamma]-secreting CD4.sup.+ helper T cells are required for antibody access to neuronal tissues in response to neurotropic virus infections. CD4 T cells enable antibody delivery to neuronal tissue Norifumi Iijima and Akiko Iwasaki investigate the mechanism of antibody-mediated protection within barrier-protected tissues using a mouse model of genital herpes infection. They find that interferon-[gamma]-secreting CD4.sup.+ helper T cells are required for antibody access to neuronal tissues in response to challenge with herpes simplex virus 2. These results point to a previously unappreciated role of CD4.sup.+ T cells in mobilizing antibodies to the peripheral sites of infection where they help to limit viral spread. Circulating antibodies can access most tissues to mediate surveillance and elimination of invading pathogens. Immunoprivileged tissues such as the brain and the peripheral nervous system are shielded from plasma proteins by the blood-brain barrier.sup.1 and blood-nerve barrier.sup.2, respectively. Yet, circulating antibodies must somehow gain access to these tissues to mediate their antimicrobial functions. Here we examine the mechanism by which antibodies gain access to neuronal tissues to control infection. Using a mouse model of genital herpes infection, we demonstrate that both antibodies and CD4 T cells are required to protect the host after immunization at a distal site. We show that memory CD4 T cells migrate to the dorsal root ganglia and spinal cord in response to infection with herpes simplex virus type 2. Once inside these neuronal tissues, CD4 T cells secrete interferon-[gamma] and mediate local increase in vascular permeability, enabling antibody access for viral control. A similar requirement for CD4 T cells for antibody access to the brain is observed after intranasal challenge with vesicular stomatitis virus. Our results reveal a previously unappreciated role of CD4 T cells in mobilizing antibodies to the peripheral sites of infection where they help to limit viral spread., Author(s): Norifumi Iijima [sup.1] , Akiko Iwasaki [sup.1] [sup.1] Author Affiliations: (1) Department of Immunobiology, Howard Hughes Medical Institute, Yale School of Medicine, New Haven, USA Main To investigate the [...]

Mitochondrial DNA stress potentiates type I interferon responses via activation of the cGAS-STING-IRF3 pathway. Mitochondria trigger innate immunity Accumulating evidence suggests that mitochondria, the organelles primarily responsible for cellular respiration and energy production, are also critical centres for antibacterial and antiviral innate immune responses. This study describes a link between mitochondrial stress and antiviral innate immunity. Specifically, mitochondrial DNA stress in herpes virus infected mice is shown to elevate interferon-stimulated gene expression, potentiate type I interferon responses and confer broad viral resistance through activation of the DNA sensor cGAS and the STING-IRF3 stress pathway. Mitochondrial DNA (mtDNA) is normally present at thousands of copies per cell and is packaged into several hundred higher-order structures termed nucleoids.sup.1. The abundant mtDNA-binding protein TFAM (transcription factor A, mitochondrial) regulates nucleoid architecture, abundance and segregation.sup.2. Complete mtDNA depletion profoundly impairs oxidative phosphorylation, triggering calcium-dependent stress signalling and adaptive metabolic responses.sup.3. However, the cellular responses to mtDNA instability, a physiologically relevant stress observed in many human diseases and ageing, remain poorly defined.sup.4. Here we show that moderate mtDNA stress elicited by TFAM deficiency engages cytosolic antiviral signalling to enhance the expression of a subset of interferon-stimulated genes. Mechanistically, we find that aberrant mtDNA packaging promotes escape of mtDNA into the cytosol, where it engages the DNA sensor cGAS (also known as MB21D1) and promotes STING (also known as TMEM173)-IRF3-dependent signalling to elevate interferon-stimulated gene expression, potentiate type I interferon responses and confer broad viral resistance. Furthermore, we demonstrate that herpesviruses induce mtDNA stress, which enhances antiviral signalling and type I interferon responses during infection. Our results further demonstrate that mitochondria are central participants in innate immunity, identify mtDNA stress as a cell-intrinsic trigger of antiviral signalling and suggest that cellular monitoring of mtDNA homeostasis cooperates with canonical virus sensing mechanisms to fully engage antiviral innate immunity., Author(s): A. Phillip West [sup.1] , William Khoury-Hanold [sup.2] , Matthew Staron [sup.2] , Michal C. Tal [sup.2] [sup.7] , Cristiana M. Pineda [sup.1] , Sabine M. Lang [sup.1] , [...]

Most successful existing vaccines rely on neutralizing antibodies, which may not require specific anatomical localization of B cells. However, efficacious vaccines that rely on T cells for protection have been [...]

CD[4.sup.+] T helper cells are well known for their role in providing critical signals during priming of cytotoxic CD[8.sup.+] T lymphocyte (CTL) responses in vivo. T-cell help is required for [...]

CD4+ T helper cells are well known for their role in providing critical signals during priming of cytotoxic CD8+ T lymphocyte (CTL) responses in vivo. T-cell help is required for the generation of primary CTL responses as well as in promoting protective CD8+ memory T-cell development. However, the role of CD4 help in the control of CTL responses at the effector stage is unknown. Here we show that fully helped effector CTLs are themselves not self-sufficient for entry into the infected tissue, but rely on the CD4+ T cells to provide the necessary cue. CD4+ T helper cells control the migration of CTL indirectly through the secretion of IFN-γ and induction of local chemokine secretion in the infected tissue. Our results reveal a previously unappreciated role of CD4 help in mobilizing effector CTL to the peripheral sites of infection where they help to eliminate infected cells. [ABSTRACT FROM AUTHOR]