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Yet, because distinguishing PAM from other types of meningitis and encephalitis can be difficult, it’s likely that many cases of PAM are simply never identified, especially in areas of the world with under-resourced healthcare systems. Because N. fowleri is a thermophilic organism, rising global temperatures will prolong growth seasons and expand compatible habitats. [...]although N. fowleri infection and PAM are not a nationally notifiable disease, there is evidence that the latitude of reported infections has broadened over the past 10 to 15 years [1]. [...]a critical component of N. fowleri’s lethal opportunism likely lies in the barrier being breached within nasal turbinates. [...]pathogenic variants of N. fowleri are resistant to downstream complement mediated lysis [16], and there is scant in vivo evidence that complement is critical to N. fowleri containment. Because neutrophils show no intrinsic chemotactic response toward N. fowleri [15], how is the alarm bell rung?

Progenitor-like CD8 + T cells mediate long-term immunity to chronic infection and cancer and respond potently to immune checkpoint blockade. These cells share transcriptional regulators with memory precursor cells, including T cell-specific transcription factor 1 (TCF1), but it is unclear whether they adopt distinct programs to adapt to the immunosuppressive environment. By comparing the single-cell transcriptomes and epigenetic profiles of CD8 + T cells responding to acute and chronic viral infections, we found that progenitor-like CD8 + T cells became distinct from memory precursor cells before the peak of the T cell response. We discovered a coexpression gene module containing Tox that exhibited higher transcriptional activity associated with more abundant active histone marks in progenitor-like cells than memory precursor cells. Moreover, thymocyte selection-associated high mobility group box protein TOX (TOX) promoted the persistence of antiviral CD8 + T cells and was required for the programming of progenitor-like CD8 + T cells. Thus, long-term CD8 + T cell immunity to chronic viral infection requires unique transcriptional and epigenetic programs associated with the transcription factor TOX. Long-lived, self-renewing ‘progenitor-like’ CD8 + T cells can arise during chronic viral infection or in cancer. Wu and colleagues identify the transcription factor TOX as essential to endow ‘stemness’ and long-term persistence in the face of chronic infection.

During chronic infection and cancer, a self-renewing CD8 + T cell subset maintains long-term immunity and is critical to the effectiveness of immunotherapy. These stem-like CD8 + T cells diverge from other CD8 + subsets early after chronic viral infection. However, pathways guarding stem-like CD8 + T cells against terminal exhaustion remain unclear. Here, we show that the gene encoding transcriptional repressor BACH2 is transcriptionally and epigenetically active in stem-like CD8 + T cells but not terminally exhausted cells early after infection. BACH2 overexpression enforced stem-like cell fate, whereas BACH2 deficiency impaired stem-like CD8 + T cell differentiation. Single-cell transcriptomic and epigenomic approaches revealed that BACH2 established the transcriptional and epigenetic programs of stem-like CD8 + T cells. In addition, BACH2 suppressed the molecular program driving terminal exhaustion through transcriptional repression and epigenetic silencing. Thus, our study reveals a new pathway that enforces commitment to stem-like CD8 + lineage and prevents an alternative terminally exhausted cell fate. Tuoqi Wu and colleagues show that the transcriptional repressor BACH2 is required early after chronic viral infection to enforce a stem-like fate in activated CD8 + T cells. BACH2 acts to suppress genes that lead to the exhausted cell state.

Secreting a continuous, and sometimes life-long antibody supply, plasma cells are the effector arm of humoral immune system. With an incredibly diverse array of binding specificities, antibodies play critical roles in homeostasis and disease. Traditional views of plasma cells have them function at a distance, relying on circulation to ferry their antibodies to peripheral tissues. However, this review focuses on plasma cells that operate locally within tissues that lack ready access to circulating antibody, specifically, we explore plasma cells that accumulate within the central nervous system (CNS) and its borders. Through both antibody secretion and immunoregulation, plasma cells impact responses to neuroinvasive pathogens, CNS-targeting autoimmune diseases, and CNS tumors. In border sites, like the meninges and olfactory mucosa, plasma cells serve to protect against CNS pathogen invasion while also mediating pathology in autoimmunity and inflammatory diseases. In considering plasma cells in and around the CNS, we discuss their localization, function, migration, local differentiation, and persistence. Importantly, we examine where gaps remain in our knowledge of CNS plasma cells and how this work will impact the prevention and treatment of CNS infection and autoimmunity.

Infections with the pathogenic free-living amoebae Naegleria fowleri can lead to life-threatening illnesses including catastrophic primary amoebic meningoencephalitis (PAM). Efficacious treatment options for these infections are lacking and the mortality rate remains >95% in the US. Glycolysis is very important for the infectious trophozoite lifecycle stage and inhibitors of glucose metabolism have been found to be toxic to the pathogen. Recently, human enolase 2 (ENO2) phosphonate inhibitors have been developed as lead agents to treat glioblastoma multiforme (GBM). These compounds, which cure GBM in a rodent model, are well-tolerated in mammals because enolase 1 (ENO1) is the predominant isoform used systemically. Here, we describe findings that demonstrate these agents are potent inhibitors of N . fowleri ENO ( Nf ENO) and are lethal to amoebae. In particular, (1-hydroxy-2-oxopiperidin-3-yl) phosphonic acid (HEX) was a potent enzyme inhibitor (IC 50 = 0.14 ± 0.04 μM) that was toxic to trophozoites (EC 50 = 0.21 ± 0.02 μM) while the reported CC 50 was >300 μM. Molecular docking simulation revealed that HEX binds strongly to the active site of Nf ENO with a binding affinity of –8.6 kcal/mol. Metabolomic studies of parasites treated with HEX revealed a 4.5 to 78-fold accumulation of glycolytic intermediates upstream of Nf ENO. Last, nasal instillation of HEX increased longevity of amoebae-infected rodents. Two days after infection, animals were treated for 10 days with 3 mg/kg HEX, followed by one week of observation. At the end of the one-week observation, eight of 12 HEX-treated animals remained alive (resulting in an indeterminable median survival time) while one of 12 vehicle-treated rodents remained, yielding a median survival time of 10.9 days. However, intranasal HEX delivery was not curative as brains of six of the eight survivors were positive for amoebae. These findings suggest that HEX requires further evaluation to develop as a lead for treatment of PAM.

BACKGROUNDPresbyosmia, or aging-related olfactory loss, occurs in a majority of humans over age 65 years, yet remains poorly understood, with no specific treatment options. The olfactory epithelium (OE) is the peripheral organ for olfaction and is subject to acquired damage, suggesting a likely site of pathology in aging. Adult stem cells reconstitute the neuroepithelium in response to cell loss under normal conditions. In aged OE, patches of respiratory-like metaplasia have been observed histologically, consistent with a failure in normal neuroepithelial homeostasis.MethodsAccordingly, we have focused on identifying cellular and molecular changes in presbyosmic OE. The study combined psychophysical testing with olfactory mucosa biopsy analysis, single-cell RNA-Sequencing (scRNA-Seq), and culture studies.ResultsWe identified evidence for inflammation-associated changes in the OE stem cells of presbyosmic patients. The presbyosmic basal stem cells exhibited increased expression of genes involved in response to cytokines or stress or the regulation of proliferation and differentiation. Using a culture model, we found that cytokine exposure drove increased TP63, a transcription factor acting to prevent OE stem cell differentiation.ConclusionsOur data suggest aging-related inflammatory changes in OE stem cells may contribute to presbyosmia via the disruption of normal epithelial homeostasis. OE stem cells may represent a therapeutic target for restoration of olfaction.FundingNIH grants DC018371, NS121067, DC016224; Office of Physician-Scientist Development, Burroughs-Wellcome Fund Research Fellowship for Medical Students Award, Duke University School of Medicine.

T cell specificity and function are linked during development, as MHC-II-specific TCR signals generate CD4 helper T cells and MHC-I-specific TCR signals generate CD8 cytotoxic T cells, but the basis remains uncertain. We now report that switching coreceptor proteins encoded by Cd4 and Cd8 gene loci functionally reverses the T cell immune system, generating CD4 cytotoxic and CD8 helper T cells. Such functional reversal reveals that coreceptor proteins promote the helper-lineage fate when encoded by Cd4, but promote the cytotoxic-lineage fate when encoded in Cd8—regardless of the coreceptor proteins each locus encodes. Thus, T cell lineage fate is determined by cis-regulatory elements in coreceptor gene loci and is not determined by the coreceptor proteins they encode, invalidating coreceptor signal strength as the basis of lineage fate determination. Moreover, we consider that evolution selected the particular coreceptor proteins that Cd4 and Cd8 gene loci encode to avoid generating functionally reversed T cells because they fail to promote protective immunity against environmental pathogens.To determine how T cell lineage fates are determined in the thymus, Singer and colleagues generated ‘FlipFlop’ mice with a functionally reversed T cell immune system that distinguishes TCR signal strength versus TCR signal duration.

NK cells confer innate immune functions. Von Andrian and colleagues show that hepatic NK cells bearing CXCR6 receptors confer antigen-specific NK cell memory that is protective against various viruses. Hepatic natural killer (NK) cells mediate antigen-specific contact hypersensitivity (CHS) in mice deficient in T cells and B cells. We report here that hepatic NK cells, but not splenic or naive NK cells, also developed specific memory of vaccines containing antigens from influenza, vesicular stomatitis virus (VSV) or human immunodeficiency virus type 1 (HIV-1). Adoptive transfer of virus-sensitized NK cells into naive recipient mice enhanced the survival of the mice after lethal challenge with the sensitizing virus but not after lethal challenge with a different virus. NK cell memory of haptens and viruses depended on CXCR6, a chemokine receptor on hepatic NK cells that was required for the persistence of memory NK cells but not for antigen recognition. Thus, hepatic NK cells can develop adaptive immunity to structurally diverse antigens, an activity that requires NK cell–expressed CXCR6.

Lymphatic defence against neurotropic viruses Microorganisms that breach the body's external defences and enter the lymphatic system are liable to be captured by the lymph nodes, and recent work showed that a subset of macrophages found in the subcapsular sinus (SCS) of lymph nodes is critical for clearance of viruses from the lymph and for initiating antiviral humoral immune responses. Now a third function for SCS macrophages has been identified: the prevention of lymph-borne neurotropic viruses from infecting the CNS. Using vesicular stomatitis virus (VSV) as a model, Iannacone et al . showed that local depletion of SCS macrophages made mice injected subcutaneously with VSV more vulnerable to the virus via a mechanism dependent on type I interferon. VSV is a relative of rabies virus typically transmitted by insect bites, causing a fatal paralytic disease in some mammals. Combined with further experiments in mice lacking the IFN-I receptor, these findings suggest that SCS macrophages are crucial gatekeepers to the CNS that prevent fatal viral neuroinvasion upon peripheral infection. Macrophages that populate the lymph nodes are known to clear viruses from the lymph and to initiate antiviral humoral immune responses. It is now shown that these macrophages also have another function: they prevent lymph-borne neurotropic viruses from entering the central nervous system. The mechanism is dependent on the production of type I interferon. Lymph nodes (LNs) capture microorganisms that breach the body’s external barriers and enter draining lymphatics, limiting the systemic spread of pathogens 1 . Recent work has shown that CD11b + CD169 + macrophages, which populate the subcapsular sinus (SCS) of LNs, are critical for the clearance of viruses from the lymph and for initiating antiviral humoral immune responses 2 , 3 , 4 . Here we show, using vesicular stomatitis virus (VSV), a relative of rabies virus transmitted by insect bites, that SCS macrophages perform a third vital function: they prevent lymph-borne neurotropic viruses from infecting the central nervous system (CNS). On local depletion of LN macrophages, about 60% of mice developed ascending paralysis and died 7–10 days after subcutaneous infection with a small dose of VSV, whereas macrophage-sufficient animals remained asymptomatic and cleared the virus. VSV gained access to the nervous system through peripheral nerves in macrophage-depleted LNs. In contrast, within macrophage-sufficient LNs VSV replicated preferentially in SCS macrophages but not in adjacent nerves. Removal of SCS macrophages did not compromise adaptive immune responses against VSV, but decreased type I interferon (IFN-I) production within infected LNs. VSV-infected macrophages recruited IFN-I-producing plasmacytoid dendritic cells to the SCS and in addition were a major source of IFN-I themselves. Experiments in bone marrow chimaeric mice revealed that IFN-I must act on both haematopoietic and stromal compartments, including the intranodal nerves, to prevent lethal infection with VSV. These results identify SCS macrophages as crucial gatekeepers to the CNS that prevent fatal viral invasion of the nervous system on peripheral infection.

Lymph nodes help clear infecting pathogens and prevent their dissemination. In the case of lymph-borne virus, this involves a particular subpopulation of macrophages that is shown to capture the viral particles and present them to B cells, leading to B cell activation. Lymph nodes prevent the systemic dissemination of pathogens such as viruses that infect peripheral tissues after penetrating the body’s surface barriers. They are also the staging ground of adaptive immune responses to pathogen-derived antigens 1 , 2 . It is unclear how virus particles are cleared from afferent lymph and presented to cognate B cells to induce antibody responses. Here we identify a population of CD11b + CD169 + MHCII + macrophages on the floor of the subcapsular sinus (SCS) and in the medulla of lymph nodes that capture viral particles within minutes after subcutaneous injection. Macrophages in the SCS translocated surface-bound viral particles across the SCS floor and presented them to migrating B cells in the underlying follicles. Selective depletion of these macrophages compromised local viral retention, exacerbated viraemia of the host, and impaired local B-cell activation. These findings indicate that CD169 + macrophages have a dual physiological function. They act as innate ‘flypaper’ by preventing the systemic spread of lymph-borne pathogens and as critical gatekeepers at the lymph–tissue interface that facilitate the recognition of particulate antigens by B cells and initiate humoral immune responses.