Pathogens and Immunity最新文献

Most vaccines against viral pathogens protect through the acquisition of immunological memory from long-lived plasma cells that produce antibodies and memory B cells that can rapidly respond upon an encounter with the pathogen or its variants. The COVID-19 pandemic and rapid deployment of effective vaccines have provided an unprecedented opportunity to study the immune response to a new yet rapidly evolving pathogen. Here we review the scientific literature and our efforts to understand antibody and B-cell responses to SARS-CoV-2 vaccines, the effect of SARSCoV-2 infection on both primary and secondary immune responses, and how repeated exposures may impact outcomes.

We consider the multiple senses of several key terms that are used to discuss the ongoing COVID-19 pandemic and clarify meanings of the corresponding concepts. Topics addressed include: 1) the meaning of immunity to an infectious agent in varying medical and scientific contexts, 2) the scientific factors that influenced the rapid generation and clinical implementation of safe and effective vaccines for COVID-19, 3) the difference between mutational abrogation of reactivity with B- or T-cell antigen receptors (immune escape) versus active interference with host immune mechanisms mediated by gene products encoded within the genome of the infectious agent (immune evasion), 4) the different ways by which the COVID-19 pandemic has "caused" deaths, and 5) briefly, the challenge of precisely defining the term pathogen.

Reprinted with permission, Cleveland Clinic Foundation ©2022. All Rights Reserved.

Background: Barriers are commonly installed in workplace situations where physical distancing cannot be maintained to reduce the risk for transmission of respiratory viruses. Although some types of barriers have been shown to reduce exposure to aerosols in laboratory-based testing, limited information is available on the efficacy of barriers in real-world settings.

Methods: In an acute care hospital, we tested the effectiveness of in-use plexiglass barriers in reducing exposure of staff to aerosolized particles. A nebulizer was used to release 5% NaCl aerosol 1 meter from staff members with and without the barrier positioned between the point of aerosol release and the hospital staff. Particle counts on the staff side of the barrier were measured using a 6-channel particle counter. A condensed moisture (fog) generating device was used to visualize the airflow patterns.

Results: Of 13 in-use barriers tested, 6 (46%) significantly reduced aerosol particle counts detected behind the barrier, 6 (46%) reduced particle counts to a modest, non-significant degree, and 1 (8%) significantly increased particle counts behind the barrier. Condensed moisture fog accumulated in the area where staff were seated behind the barrier that increased particle exposure, but not behind the other barriers. After repositioning the ineffective barrier, the condensed moisture fog no longer accumulated behind the barrier and aerosol exposure was reduced.

Conclusion: In real-world settings, plexiglass barriers vary widely in effectiveness in reducing staff exposure to aerosols, and some barriers may increase risk for exposure if not positioned correctly. Devices that visualize airflow patterns may be useful as simple tools to assess barriers.

Drug-resistant Gram-negative bacterial pathogens are an increasingly serious health threat causing worldwide nosocomial infections with high morbidity and mortality. Of these, the most prevalent and severe are Pseudomonas aeruginosa, Klebsiella pneumoniae, Escherichia coli, Acinetobacter baumannii, and Salmonella typhimurium. The extended use of antibiotics has led to the emergence of multidrug resistance in these bacteria. Drug-inactivating enzymes produced by these bacteria, as well as other resistance mechanisms, render drugs ineffective and make treatment of such infections more difficult and complicated. This makes the development of novel antimicrobial agents an urgent necessity. Bacteriophages, which are bacteria-killing viruses first discovered in 1915, have been used as therapeutic antimicrobials in the past, but their use was abandoned due to the widespread availability of antibiotics in the 20th century. The emergence, however, of drug-resistant pathogens has re-affirmed the need for bacteriophages as therapeutic strategies. This review describes the use of bacteriophages as novel agents to combat this rapidly emerging public health crisis by comprehensively enumerating and discussing the innovative use of bacteriophages in both animal models and in patients infected by Gram-negative bacteria.

Background: Mucosal-associated invariant T (MAIT) cells are innate-like T cells enriched in the mucosa with capacity for B-cell help. We hypothesize that targeting MAIT cells, using a MAIT-activating ligand as an adjuvant, could improve mucosal vaccine responses to bacterial pathogens such as Vibrio cholerae.

Methods: We utilized murine models of V. cholerae vaccination to test the adjuvant potential of the MAIT-activating ligand, 5-(2-oxopropylideneamino)-6-D-ribitylaminouracil (5-OP-RU). We measured V. cholerae-specific antibody and antibody-secreting cell responses and used flow cytometry to examine MAIT-cell and B-cell phenotype, in blood, bronchoalveolar lavage fluid (BALF), and mucosal tissues, following intranasal vaccination with live V. cholerae O1 or a V. cholerae O1 polysaccharide conjugate vaccine.

Results: We report significant expansion of MAIT cells in the lungs (P < 0.001) and BALF (P < 0.001) of 5-OP-RU treated mice, and higher mucosal (BALF, P = 0.045) but not systemic (serum, P = 0.21) V. cholerae O-specific-polysaccharide IgG responses in our conjugate vaccine model when adjuvanted with low-dose 5-OP-RU. In contrast, despite significant MAIT cell expansion, no significant differences in V. cholerae-specific humoral responses were found in our live V. cholerae vaccination model.

Conclusions: Using a murine model, we demonstrate the potential, as well as the limitations, of targeting MAIT cells to improve antibody responses to mucosal cholera vaccines. Our study highlights the need for future research optimizing MAIT-cell targeting for improving mucosal vaccines.

Background: The continued emergence of SARS-CoV-2 variants has caused concern that a constantly evolving virus will escape vaccines and antibody therapies. New approaches are needed.

Methods: We created and manufactured an ACE2 extracellular domain (ECD) fragment Fc fusion drug candidate, G921, and engineered the compound for enhanced delivery of drug to peripheral tissues by minimizing the size of the ACE2 ECD and by incorporating an Fc domain to enhance transcytosis. G921 was assessed for binding, neutralization, in vivo anti-inflammatory effect, and pharmacokinetic profile.

Results: G921 was expressed as an IgG4 Fc fusion protein presenting two ACE2 domains to ACE2 ligands while avoiding risk of infection via antibody-dependent enhancement. G921 strongly binds to the SARS-CoV-2 Wuhan-Hu-1 spike protein and demonstrates further diminished off rate to the spike protein from each of the currently identified variants of concern. G921 demonstrates ACE2 enzymatic activity comparable to positive control and binding to the neonatal Fc receptor (FcRn) without binding to low affinity Fc-gamma receptors (FcγRs). G921 is effective in a concentration-dependent manner in a focus reduction neutralization assay with EC₅₀=16.3±4.2 µg/mL without cytotoxicity in Vero E6 cells when tested at 200 µg/mL in an MTS cell proliferation assay. G921 demonstrates statistically significant reduction of lung inflammation in relevant models of both SARS-CoV-2 and influenza. The pharmacokinetic profile demonstrated dose-dependent exposure with a multi-day half-life in monkeys and rats.

Conclusion: G921 data are consistent with both antiviral and anti-inflammatory modes of action. G921 is a novel approach for the prevention and treatment of COVID-19 and possible other diseases characterized by deficiency of ACE2.

Background: Efforts to understand the impact of SARS-CoV-2 variants, vaccine status, and treatment on the development and persistence of Long COVID have intensified.

Methods: We report 4 sequential cases from a post-COVID cohort study demonstrating variability in outcomes following differentially timed nirmatrelvir therapy, received as part of clinical care.

Results: In the first case, the participant experienced symptomatic rebound and developed Long COVID despite early initiation of antiviral therapy. In the next 2 cases, participants reported improvement in persistent COVID symptoms when nirmatrelvir was taken 25 and 60 days following initial symptom onset. In the final case, an individual with presumed Long COVID for 2 years reported substantial improvement in chronic symptoms when taking nirmatrelvir following SARS-CoV-2 re-infection.

Conclusions: These anecdotes suggest that systematic study of antiviral therapy for Long COVID is warranted.

Background: Murine experimental cerebral malaria studies suggest both protective and deleterious central nervous system effects from alterations in the interleukin-33 (IL-33)/ST2 pathway.

Methods: We assessed whether soluble ST2 (sST2) was associated with neuronal injury or cognitive impairment in a cohort of Ugandan children with cerebral malaria (CM, n=224) or severe malarial anemia (SMA, n=193).

Results: Plasma concentrations of sST2 were higher in children with CM than in children with SMA or in asymptomatic community children. Cerebrospinal fluid (CSF) sST2 levels were elevated in children with CM compared with North American children. Elevated plasma and CSF ST2 levels in children with CM correlated with increased endothelial activation and increased plasma and CSF levels of tau, a marker of neuronal injury. In children with CM who were ≥5 years of age at the time of their malaria episode, but not in children <5 years of age, elevated risk factor-adjusted plasma levels of sST2 were associated with worse scores for overall cognitive ability and attention over a 2-year follow-up.

Conclusions: The study findings suggest that sST2 may contribute to neuronal injury and long-term neurocognitive impairment in older children with CM.

Background: Clinical studies suggest that doxycycline poses a low risk for promotion of Clostridioides difficile infection, but the microbiologic explanation for this finding is unclear.

Methods: Mice treated with oral doxycycline, oral azithromycin, subcutaneous ceftriaxone, doxycycline plus ceftriaxone, or azithromycin plus ceftriaxone were challenged with 10⁴ colony-forming units of 2 different C. difficile strains on day 2 of 5 of treatment. The concentration of C. difficile was measured in stool 2 and 5 days after challenge. The impact of the treatments on the microbiota was assessed by sequencing.

Results: Doxycycline and azithromycin treatment did not promote colonization by either C. difficile strain in comparison to saline controls. Doxycycline treatment significantly reduced ceftriaxone-induced overgrowth of a C. difficile strain with doxycycline minimum-inhibitory concentration (MIC) of 0.06 µg/mL (P<0.01) but not a strain with doxycycline MIC of 48 µg/mL (P>0.05); azithromycin treatment did not reduce ceftriaxone-induced overgrowth of either strain. 16S rRNA amplicon sequencing revealed significantly lower bacterial diversity in the stool of ceftriaxone-treated mice, in comparison to doxycycline-treated and azithromycin-treated mice.

Conclusions: These findings suggest that doxycycline may have a low propensity to promote C. difficile colonization because it causes relatively limited alteration of the indigenous microbiota that provide colonization resistance and because it provides inhibitory activity against some C. difficile strains.