Antigen non-specific CD8+ T cells accelerate cognitive decline in aged mice following respiratory coronavirus infection.

Primarily a respiratory infection, numerous patients infected with SARS-CoV-2 present with neurologic symptoms, some continuing long after viral clearance as a persistent symptomatic phase termed "long COVID". Advanced age increases the risk of severe disease, as well as incidence of long COVID. We hypothesized that perturbations in the aged immune response predispose elderly individuals to severe coronavirus infection and post-infectious sequelae. Using a murine model of respiratory coronavirus, mouse hepatitis virus strain A59 (MHV-A59), we found that aging increased clinical illness and lethality to MHV infection, with aged animals harboring increased virus in the brain during acute infection. This was coupled with an unexpected increase in activated CD8+ T cells within the brains of aged animals but reduced antigen specificity of those CD8+ T cells. Aged animals demonstrated spatial learning impairment following MHV infection, which correlated with increased neuronal cell death and reduced neuronal regeneration in aged hippocampus. Using primary cell culture, we demonstrated that activated CD8+ T cells induce neuronal death, independent of antigen-specificity. Specifically, higher levels of CD8+ T cell-derived IFN-γ correlated with neuronal death. These results support the evidence that CD8+ T cells in the brain directly contribute to cognitive dysfunction following coronavirus infection in aged individuals.

Bordetella bronchiseptica-Mediated Interference Prevents Influenza A Virus Replication in the Murine Nasal Cavity.

Colonization resistance, also known as pathogen interference, describes the ability of a colonizing microbe to interfere with the ability of an incoming microbe to establish infection, and in the case of pathogenic organisms, cause disease in a susceptible host. Furthermore, colonization-associated dysbiosis of the commensal microbiota can alter host immunocompetence and infection outcomes. Here, we investigated the role of Bordetella bronchiseptica nasal colonization and associated disruption of the nasal microbiota on the ability of influenza A virus to establish infection in the murine upper respiratory tract. Targeted sequencing of the microbial 16S rRNA gene revealed that B. bronchiseptica colonization of the nasal cavity efficiently displaced the resident commensal microbiota-the peak of this effect occurring 7 days postcolonization-and was associated with reduced influenza associated-morbidity and enhanced recovery from influenza-associated clinical disease. Anti-influenza A virus hemagglutinin-specific humoral immune responses were not affected by B. bronchiseptica colonization, although the cellular influenza PA-specific CD8+ immune responses were dampened. Notably, influenza A virus replication in the nasal cavity was negated in B. bronchiseptica-colonized mice. Collectively, this work demonstrates that B. bronchiseptica-mediated pathogen interference prevents influenza A virus replication in the murine nasal cavity. This may have direct implications for controlling influenza A virus replication in, and transmission events originating from, the upper respiratory tract. IMPORTANCE The interplay of microbial species in the upper respiratory tract is important for the ability of an incoming pathogen to establish and, in the case of pathogenic organisms, cause disease in a host. Here, we demonstrate that B. bronchiseptica efficiently colonizes and concurrently displaces the commensal nasal cavity microbiota, negating the ability of influenza A virus to establish infection. Furthermore, B. bronchiseptica colonization also reduced influenza-associated morbidity and enhanced recovery from influenza-associated disease. Collectively, this study indicates that B. bronchiseptica-mediated interference prevents influenza A virus replication in the upper respiratory tract. This result demonstrates the potential for respiratory pathogen-mediated interference to control replication and transmission dynamics of a clinically important respiratory pathogen like influenza A virus.

The role of antiviral CD8+ T cells in cognitive impairment.

The impact of the immune system on the etiopathogenesis of neurodegenerative diseases, including Alzheimer's disease, is a rapidly growing area of investigation. Evidence from human patients and animal models implicates neurotropic viral infections, and specifically the antiviral immune response of brain-infiltrating CD8+ T cells, as potential drivers of disease pathology. While infiltration and retention of CD8+ T cells within the brain following viral infection is associated with improved survival, CD8+ T cells also contribute to neuronal death and gliosis which underlie cognitive impairment in several disease models. Here we review the role of antiviral CD8+ T cells as potential mediators of cognitive impairment and highlight the mechanisms by which brain-resident CD8+ T cells may contribute to neurodegenerative disease pathology.

Microbial Infections Are a Risk Factor for Neurodegenerative Diseases.

Neurodegenerative diseases, such as Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis, comprise a family of disorders characterized by progressive loss of nervous system function. Neuroinflammation is increasingly recognized to be associated with many neurodegenerative diseases but whether it is a cause or consequence of the disease process is unclear. Of growing interest is the role of microbial infections in inciting degenerative neuroinflammatory responses and genetic factors that may regulate those responses. Microbial infections cause inflammation within the central nervous system through activation of brain-resident immune cells and infiltration of peripheral immune cells. These responses are necessary to protect the brain from lethal infections but may also induce neuropathological changes that lead to neurodegeneration. This review discusses the molecular and cellular mechanisms through which microbial infections may increase susceptibility to neurodegenerative diseases. Elucidating these mechanisms is critical for developing targeted therapeutic approaches that prevent the onset and slow the progression of neurodegenerative diseases.

Enhanced generation of influenza-specific tissue resident memory CD8 T cells in NK-depleted mice.

Natural Killer (NK) cells are among the first effectors to directly contact influenza and influenza-infected cells and their activation affects not only their intrinsic functions, but also subsequent CD8+ T cell responses. We utilized a NK cell depletion model to interrogate the contribution of NK cells to the development of anti-influenza CD8+ T cell memory. NK cell ablation increased the number of influenza-specific memory CD8+ T cells in the respiratory tract and lung-draining lymph node. Interestingly, animals depleted of NK cells during primary influenza infection were protected as well as their NK-intact counterparts despite significantly fewer reactivated CD8+ T cells infiltrating the respiratory tract after lethal, heterosubtypic challenge. Instead, protection in NK-deficient animals seems to be conferred by rapid reactivation of an enlarged pool of lung tissue-resident (TRM) memory cells within two days post challenge. Further interrogation of how NK cell ablation enhances respiratory TRM indicated that TRM development is independent of global and NK cell derived IFN-γ. These data suggest that reduction in NK cell activation after vaccination with live, non-lethal influenza virus increases compartmentalized, broadly protective memory CD8+ T cell generation and decreases the risk of CD8+ T cell-mediated pathology following subsequent influenza infections.

Placenta-specific 8 limits IFNγ production by CD4 T cells in vitro and promotes establishment of influenza-specific CD8 T cells in vivo.

During type 1 immune responses, CD4 T helper 1 (Th1) cells and CD8 T cells are activated via IL-12 and contribute to the elimination of intracellular pathogens through interferon gamma (IFNγ) production. In this study, we identified Placenta-specific 8 (Plac8) as a gene that is uniquely expressed in Th1 CD4 T cells relative to other CD4 T cell subsets and hypothesized that Plac8 may represent a novel therapeutic target in Th1 CD4 T cells. First, we determined that Plac8 mRNA in CD4 T cells was induced following IL-12 stimulation via an indirect route that required new protein synthesis. Upon evaluating the functional relevance of Plac8 expression in Th1 CD4 T cells, we discovered that Plac8 was important for suppressing IFNγ mRNA and protein production by CD4 T cells 24 hours after IL-12 stimulation, however Plac8 did not contribute to pathogenic CD4 T cell function during two models of intestinal inflammation. We also noted relatively high basal expression of Plac8 in CD8 T cells which could be further induced following IL-12 stimulation in CD8 T cells. Furthermore, Plac8 expression was important for establishing an optimal CD8 T cell response against influenza A virus via a T cell-intrinsic manner. Altogether, these results implicate Plac8 as a potential regulator of Th1 CD4 and CD8 T cell responses during Th1 T cell-driven inflammation.

The Respiratory Environment Diverts the Development of Antiviral Memory CD8 T Cells.

Our understanding of memory CD8+ T cells has been largely derived from acute, systemic infection models. However, memory CD8+ T cells generated from mucosal infection exhibit unique properties and, following respiratory infection, are not maintained in the lung long term. To better understand how infection route modifies memory differentiation, we compared murine CD8+ T cell responses to a vesicular stomatitis virus (VSV) challenge generated intranasally (i.n.) or i.v. The i.n. infection resulted in greater peak expansion of VSV-specific CD8+ T cells. However, this numerical advantage was rapidly lost during the contraction phase of the immune response, resulting in memory CD8+ T cell numerical deficiencies when compared with i.v. infection. Interestingly, the antiviral CD8+ T cells generated in response to i.n. VSV exhibited a biased and sustained proportion of early effector cells (CD127loKLRG1lo) akin to the developmental program favored after i.n. influenza infection, suggesting that respiratory infection broadly favors an incomplete memory differentiation program. Correspondingly, i.n. VSV infection resulted in lower CD122 expression and eomesodermin levels by VSV-specific CD8+ T cells, further indicative of an inferior transition to bona fide memory. These results may be due to distinct (CD103+CD11b+) dendritic cell subsets in the i.n. versus i.v. T cell priming environments, which express molecules that regulate T cell signaling and the balance between tolerance and immunity. Therefore, we propose that distinct immunization routes modulate both the quality and quantity of antiviral effector and memory CD8+ T cells in response to an identical pathogen and should be considered in CD8+ T cell-based vaccine design.

Incomplete Memories: The Natural Suppression of Tissue-Resident Memory CD8 T Cells in the Lung.

The yearly, cyclic impact of viruses like influenza on human health and the economy is due to the high rates of mutation of traditional antibody targets, which negate any preexisting humoral immunity. However, the seasonality of influenza infections can equally be attributed to an absent or defective memory CD8 T cell response since the epitopes recognized by these cells are derived from essential virus proteins that mutate infrequently. Experiments in mouse models show that protection from heterologous influenza infection is temporally limited and conferred by a population of tissue-resident memory (TRM) cells residing in the lung and lung airways. TRM are elicited by a diverse set of pathogens penetrating mucosal barriers and broadly identified by extravascular staining and expression of the activation and adhesion molecules CD69 and CD103. Interestingly, lung TRM fail to express these molecules, which could limit tissue retention, resulting in airway expulsion or death with concomitant loss of heterologous protection. Here, we make the case that respiratory infections uniquely evoke a form of natural immunosuppression whereby specific cytokines and cell-cell interactions negatively impact memory cell programming and differentiation. Respiratory memory is not only short-lived but most of the memory cells in the lung parenchyma may not be bona fide TRM. Given the quantity of microbes humans inhale over a lifetime, limiting cellular residence could be a mechanism employed by the respiratory tract to preserve organismal vitality. Therefore, successful efforts to improve respiratory immunity must carefully and selectively breach these inherent tissue barriers.