The COVID-19 pandemic accelerated recognition of airborne transmission of respiratory infections. Despite improved mechanistic understanding, our ability to predict the risk of infection in a given scenario remains limited owing, in part, to high heterogeneity in factors involved in transmission. The goal of this work is to quantify variability in factors that control risk of airborne virus transmission in the built environment. Using SARS-CoV-2 as a model, we conducted a narrative review on transmission via inhalable respiratory particles (<100 µm). We divided transmission into three key processes: emission of virus in respiratory particles from an infected individual (the source) into the air; transport and decay of virus in the environment; and deposition and infection in a new host (the receiver). Among the source-related factors, we found large variabilities spanning seven or more orders of magnitude. For example, the rate of respiratory emissions from an infected individual ranges from 1 to > 107 particles/s, depending in part on the type of respiratory activity and individual physiological factors. Unexplained inter-individual variations, such as those defining “superemitters,” introduce additional uncertainties. We also found considerable variability in the physical and biological decay of virus-laden particles, as they move from the source to the receiver. The air exchange rate, which controls physical loss of particles by ventilation, ranges from 0.01 to > 20 air changes per hour in typical buildings. Lastly, upon inhalation, the efficiency and site of virus deposition vary with the physiological state of the receiver. Their immunological status further influences whether infection is established. Overall, we found the largest variability in the rate of particle emissions and viral load of respiratory fluid. These two factors determine the amount of virus released into the air by an infected person, which is a critical indicator of the potential for onward transmission. Predicting the risk of infection in a specific scenario remains challenging due to the combined effects of variability in key determinants.
HLA class I alleles confer a striking risk for T cell-mediated drug hypersensitivity, yet positive predictive values are low-typically under 10% and as low as 0.12% for some drug-HLA pairs. We propose that persistent, human-adapted pathogens-notably herpesviruses-focus postnatal immune memory on conserved epitopes in the tissue niches where viral control occurs (the Keystone Epitope Theory). The phylogenetic basis for this proposal is that herpesviruses and their vertebrate hosts have co-adapted over hundreds of millions of years, and that this co-evolutionary relationship is replayed ontogenetically as each individual acquires these infections and builds tissue-specific immune memory. When a drug-altered self-peptide approximates the geometry of such a target and is presented by the same risk HLA in the same niche at sufficient density, pre-existing tissue-resident memory T cells (TRM) may be recruited, breaching local regulatory equilibria and driving immunopathology. We synthesize three strands of evidence: (i) heterologous immunity, in which virus-imprinted TRM cross-recognize drug-modified self; (ii) antigen presentation in the same tissue where antiviral memory already resides, which helps explain why injury is tissue-restricted; and (iii) public and private TCR solutions that bridge viral and self-targets. Beginning with T cell-mediated drug hypersensitivity as an empirical anchor, we extend this framework to EBV-associated multiple sclerosis and transplant rejection and conclude with proposed experimental validation strategies that may be applicable more broadly to T cell-mediated hypersensitivity and autoimmunity.
We propose that persistent, human-adapted DNA organisms shape postnatal immunity by focusing responses on functionally constrained epitopes within tissue niches. Here, we examine rapidly evolving RNA viruses and tumors through that lens. We propose that their persistence is promoted by 2 coupled mechanisms: (i) immunodominance steering toward mutable “decoy” epitopes that contribute little to durable control, and (ii) antigen display control that reduces cytotoxic T lymphocyte (CTL) recognition while preserving inhibitory natural killer (NK) receptor engagement, for example via HIV Nef/Vpu effects on HLA-A and HLA-B and through HLA-E/NKG2A pathways. Tumors show analogous vulnerabilities through altered class I expression and reinforcement of inhibitory signaling. Using HIV as the primary model, we distinguish HLA-associated viral adaptation mechanisms and highlight evidence consistent with a subset of adaptations that preserve detectable T-cell recognition while being associated with reduced antiviral effector function. We then consider the degree to which this framework can be extended to hepatitis C virus (HCV), influenza, SARS-CoV-2, and tumor immunoediting. We conclude with 3 vaccine design principles: prioritize epitopes where substitutions carry measurable fitness costs, avoid immunogens dominated by mutable targets, and account for antigen presentation context and inhibitory NK signaling when evaluating epitope choice. We distinguish established observations from testable predictions and outline experiments needed to evaluate the framework. We frame the analysis conditionally on the keystone-imprinting premise, which is developed in companion work.
Background: The immunopathogenesis of actinomycetoma, a chronic granulomatous infection caused primarily by Nocardia brasiliensis, involves poorly defined mechanisms sustaining its characteristic cyclical inflammation. Methods: Using MCdeficient KitW-sh/W-sh mice, this study investigated the role of mast cells (MCs) in a murine model of actinomycetoma. Clinical progression, bacterial burden, histopathology, and lesional leukocyte infiltration were analyzed at 30 and 72 days postinfection, and bone marrowderived MCs were challenged in vitro with Nocardia brasiliensis to assess activation. Results: MC-deficient mice exhibited a significant increase in bacterial load concomitant with attenuated late-phase (72-day) inflammation, characterized by reduced lesional neutrophilia and lymphocytic infiltration. Furthermore, MC absence disrupted the characteristic morphology of bacterial grains. In vitro, N. brasiliensis induced potent MC degranulation and pro-inflammatory cytokine release. Conclusions: These data demonstrate that MCs are directly activated by N. brasiliensis and contribute to a delayed protective immune response, modulating late-stage inflammatory containment and bacterial clearance in experimental mycetoma.
Background: Mucosal chemokines (eg, CCL25, CCL28, CXCL14, and CXCL17) play key roles in protecting mucosal surfaces against invading infectious pathogens. However, their specific contributions to protection against genital herpes remain to be fully elucidated. Here, we investigated the role of CXCL14 as a mediator of mucosal immunity against genital HSV-2 infection and disease. Methods: CXCL14 expression was analyzed in HSV-specific CD8+ T cells from HSV-2–infected asymptomatic and symptomatic women, in primary human vaginal epithelial cells, and in a murine genital HSV-2 infection model. CXCL14(–/–) deficient mice and wild-type (WT) mice were compared for genital disease severity, vaginal viral loads, survival, immune cell recruitment, and T-cell effector function following intravaginal HSV-2 infection. Chromatin immunoprecipitation assays were performed to identify transcription factors binding to the CXCL14 promoter after HSV-2 infection. Results: CXCL14 was homeostatically expressed at the genital tract mucosal surface, and HSV-specific CD8+ T cells from HSV-2–infected asymptomatic women expressed significantly higher levels of CXCL14 than those from symptomatic women. HSV-2 infection rapidly induced CXCL14 transcription and production in primary human vaginal epithelial cells and in murine vaginal mucocutaneous tissue. CXCL14(–/–) mice developed more severe genital lesions, higher vaginal viral loads, and lower survival compared to WT mice. In addition, CXCL14 deficiency impaired the recruitment of natural killer (NK) cells, neutrophils, and CD44+CD62L– effector memory CD4+ and CD8+ T cells to the infected vaginal mucosa. It reduced T cell effector functions, including production of IFN-γ, TNF-α, and Granzyme B. Mechanistically, NF-κB and OCT-1 transcription factors bound to the CXCL14 promoter within hours of HSV-2 infection. Conclusions: Our findings demonstrate that NF-κB- and OCT-1–driven CXCL14 expression is crucial for orchestrating early innate and T-cell responses that protect against genital HSV-2 infection and disease. These results suggest that CXCL14 is an important immunoregulatory chemokine triggered early after epithelial viral infection, facilitating the induction of effective mucosal protective immunity against genital herpes.
