High frequencies of alpha common cold coronavirus/SARS-CoV-2 cross-reactive functional CD4+ and CD8+ memory T cells are associated with protection from symptomatic and fatal SARS-CoV-2 infections in unvaccinated COVID-19 patients.

Background: Cross-reactive SARS-CoV-2-specific memory CD4+ and CD8+ T cells are present in up to 50% of unexposed, pre-pandemic, healthy individuals (UPPHIs). However, the characteristics of cross-reactive memory CD4+ and CD8+ T cells associated with subsequent protection of asymptomatic coronavirus disease 2019 (COVID-19) patients (i.e., unvaccinated individuals who never develop any COVID-19 symptoms despite being infected with SARS-CoV-2) remains to be fully elucidated. Methods: This study compares the antigen specificity, frequency, phenotype, and function of cross-reactive memory CD4+ and CD8+ T cells between common cold coronaviruses (CCCs) and SARS-CoV-2. T-cell responses against genome-wide conserved epitopes were studied early in the disease course in a cohort of 147 unvaccinated COVID-19 patients who were divided into six groups based on the severity of their symptoms. Results: Compared to severely ill COVID-19 patients and patients with fatal COVID-19 outcomes, the asymptomatic COVID-19 patients displayed significantly: (i) higher rates of co-infection with the 229E alpha species of CCCs (α-CCC-229E); (ii) higher frequencies of cross-reactive functional CD134+CD137+CD4+ and CD134+CD137+CD8+ T cells that cross-recognized conserved epitopes from α-CCCs and SARS-CoV-2 structural, non-structural, and accessory proteins; and (iii) lower frequencies of CCCs/SARS-CoV-2 cross-reactive exhausted PD-1+TIM3+TIGIT+CTLA4+CD4+ and PD-1+TIM3+TIGIT+CTLA4+CD8+ T cells, detected both ex vivo and in vitro. Conclusions: These findings (i) support a crucial role of functional, poly-antigenic α-CCCs/SARS-CoV-2 cross-reactive memory CD4+ and CD8+ T cells, induced following previous CCCs seasonal exposures, in protection against subsequent severe COVID-19 disease and (ii) provide critical insights into developing broadly protective, multi-antigen, CD4+, and CD8+ T-cell-based, universal pan-Coronavirus vaccines capable of conferring cross-species protection.

A Broad-Spectrum Multi-Antigen mRNA/LNP-Based Pan-Coronavirus Vaccine Induced Potent Cross-Protective Immunity Against Infection and Disease Caused by Highly Pathogenic and Heavily Spike-Mutated SARS-CoV-2 Variants of Concern in the Syrian Hamster Model.

The first-generation Spike-alone-based COVID-19 vaccines have successfully contributed to reducing the risk of hospitalization, serious illness, and death caused by SARS-CoV-2 infections. However, waning immunity induced by these vaccines failed to prevent immune escape by many variants of concern (VOCs) that emerged from 2020 to 2024, resulting in a prolonged COVID-19 pandemic. We hypothesize that a next-generation Coronavirus (CoV) vaccine incorporating highly conserved non-Spike SARS-CoV-2 antigens would confer stronger and broader cross-protective immunity against multiple VOCs. In the present study, we identified ten non-Spike antigens that are highly conserved in 8.7 million SARS-CoV-2 strains, twenty-one VOCs, SARS-CoV, MERS-CoV, Common Cold CoVs, and animal CoVs. Seven of the 10 antigens were preferentially recognized by CD8+ and CD4+ T-cells from unvaccinated asymptomatic COVID-19 patients, irrespective of VOC infection. Three out of the seven conserved non-Spike T cell antigens belong to the early expressed Replication and Transcription Complex (RTC) region, when administered to the golden Syrian hamsters, in combination with Spike, as nucleoside-modified mRNA encapsulated in lipid nanoparticles (LNP) (i.e., combined mRNA/LNP-based pan-CoV vaccine): (i) Induced high frequencies of lung-resident antigen-specific CXCR5+CD4+ T follicular helper (TFH) cells, GzmB+CD4+ and GzmB+CD8+ cytotoxic T cells (TCYT), and CD69+IFN-γ+TNFα+CD4+ and CD69+IFN-γ+TNFα+CD8+ effector T cells (TEFF); and (ii) Reduced viral load and COVID-19-like symptoms caused by various VOCs, including the highly pathogenic B.1.617.2 Delta variant and the highly transmittable heavily Spike-mutated XBB1.5 Omicron sub-variant. The combined mRNA/LNP-based pan-CoV vaccine could be rapidly adapted for clinical use to confer broader cross-protective immunity against emerging highly mutated and pathogenic VOCs.

Genome-Wide B Cell, CD4+, and CD8+ T Cell Epitopes That Are Highly Conserved between Human and Animal Coronaviruses, Identified from SARS-CoV-2 as Targets for Preemptive Pan-Coronavirus Vaccines.

Over the last two decades, there have been three deadly human outbreaks of coronaviruses (CoVs) caused by SARS-CoV, MERS-CoV, and SARS-CoV-2, which has caused the current COVID-19 global pandemic. All three deadly CoVs originated from bats and transmitted to humans via various intermediate animal reservoirs. It remains highly possible that other global COVID pandemics will emerge in the coming years caused by yet another spillover of a bat-derived SARS-like coronavirus (SL-CoV) into humans. Determining the Ag and the human B cells, CD4+ and CD8+ T cell epitope landscapes that are conserved among human and animal coronaviruses should inform in the development of future pan-coronavirus vaccines. In the current study, using several immunoinformatics and sequence alignment approaches, we identified several human B cell and CD4+ and CD8+ T cell epitopes that are highly conserved in 1) greater than 81,000 SARS-CoV-2 genome sequences identified in 190 countries on six continents; 2) six circulating CoVs that caused previous human outbreaks of the common cold; 3) nine SL-CoVs isolated from bats; 4) nine SL-CoV isolated from pangolins; 5) three SL-CoVs isolated from civet cats; and 6) four MERS strains isolated from camels. Furthermore, the identified epitopes: 1) recalled B cells and CD4+ and CD8+ T cells from both COVID-19 patients and healthy individuals who were never exposed to SARS-CoV-2, and 2) induced strong B cell and T cell responses in humanized HLA-DR1/HLA-A*02:01 double-transgenic mice. The findings pave the way to develop a preemptive multiepitope pan-coronavirus vaccine to protect against past, current, and future outbreaks.

Genome-Wide Asymptomatic B-Cell, CD4 + and CD8 + T-Cell Epitopes, that are Highly Conserved Between Human and Animal Coronaviruses, Identified from SARS-CoV-2 as Immune Targets for Pre-Emptive Pan-Coronavirus Vaccines.

Over the last two decades, there have been three deadly human outbreaks of Coronaviruses (CoVs) caused by emerging zoonotic CoVs: SARS-CoV, MERS-CoV, and the latest highly transmissible and deadly SARS-CoV-2, which has caused the current COVID-19 global pandemic. All three deadly CoVs originated from bats, the natural hosts, and transmitted to humans via various intermediate animal reservoirs. Because there is currently no universal pan-Coronavirus vaccine available, two worst-case scenarios remain highly possible: (1) SARS-CoV-2 mutates and transforms into a seasonal "flu-like" global pandemic; and/or (2) Other global COVID-like pandemics will emerge in the coming years, caused by yet another spillover of an unknown zoonotic bat-derived SARS-like Coronavirus (SL-CoV) into an unvaccinated human population. Determining the antigen and epitope landscapes that are conserved among human and animal Coronaviruses as well as the repertoire, phenotype and function of B cells and CD4 + and CD8 + T cells that correlate with resistance seen in asymptomatic COVID-19 patients should inform in the development of pan-Coronavirus vaccines 1 . In the present study, using several immuno-informatics and sequence alignment approaches, we identified several human B-cell, CD4 + and CD8 + T cell epitopes that are highly conserved in: ( i ) greater than 81,000 SARS-CoV-2 human strains identified to date in 190 countries on six continents; ( ii ) six circulating CoVs that caused previous human outbreaks of the "Common Cold"; ( iii ) five SL-CoVs isolated from bats; ( iv ) five SL-CoV isolated from pangolins; ( v ) three SL-CoVs isolated from Civet Cats; and ( vi ) four MERS strains isolated from camels. Furthermore, we identified cross-reactive asymptomatic epitopes that: ( i ) recalled B cell, CD4 + and CD8 + T cell responses from both asymptomatic COVID-19 patients and healthy individuals who were never exposed to SARS-CoV-2; and ( ii ) induced strong B cell and T cell responses in "humanized" Human Leukocyte Antigen (HLA)-DR/HLA-A*02:01 double transgenic mice. The findings herein pave the way to develop a pre-emptive multi-epitope pan-Coronavirus vaccine to protect against past, current, and potential future outbreaks.

Determinants of COVID-19 disease severity in patients with cancer.

As of 10 April 2020, New York State had 180,458 cases of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and 9,385 reported deaths. Patients with cancer comprised 8.4% of deceased individuals1. Population-based studies from China and Italy suggested a higher coronavirus disease 2019 (COVID-19) death rate in patients with cancer2,3, although there is a knowledge gap as to which aspects of cancer and its treatment confer risk of severe COVID-194. This information is critical to balance the competing safety considerations of reducing SARS-CoV-2 exposure and cancer treatment continuation. From 10 March to 7 April 2020, 423 cases of symptomatic COVID-19 were diagnosed at Memorial Sloan Kettering Cancer Center (from a total of 2,035 patients with cancer tested). Of these, 40% were hospitalized for COVID-19, 20% developed severe respiratory illness (including 9% who required mechanical ventilation) and 12% died within 30 d. Age older than 65 years and treatment with immune checkpoint inhibitors (ICIs) were predictors for hospitalization and severe disease, whereas receipt of chemotherapy and major surgery were not. Overall, COVID-19 in patients with cancer is marked by substantial rates of hospitalization and severe outcomes. The association observed between ICI and COVID-19 outcomes in our study will need further interrogation in tumor-specific cohorts.

Nontuberculous Mycobacterial Infections After Silicone Breast Implant Reconstruction Emphasize a Diversity of Infecting Mycobacteria.

Postsurgical skin and soft tissue infections (SSTIs) caused by nontuberculous mycobacteria (NTM) are uncommon, indolent, difficult to treat, and often mimic pyogenic bacterial infections. Here we present 3 cases of NTM infections following placement of silicone implants for reconstructive breast surgery. These cases emphasize the importance of a high index of suspicion for NTM in patients with SSI after a prosthetic reconstruction refractory to conventional antibiotic therapy and the importance of early investigation with mycobacterial-specific diagnostics.

Clinical and radiographic differentiation of lung nodules caused by mycobacteria and lung cancer: a case-control study.

BACKGROUND: Lung nodules caused by mycobacteria can resemble lung cancer on chest imaging. The advent of lung cancer screening with low-dose Computed Tomography is accompanied by high false-positive rates, making it necessary to establish criteria to differentiate malignant from benign nodules. METHODS: We conducted a retrospective case-control study of 52 patients with mycobacterial lung nodules and 139 patients with lung cancer, diagnosed between 2010 and 2012. We compared clinical and radiographic characteristics to identify predictors of disease by univariate and multivariate analysis. The discriminatory power of maximum Standardized Uptake Values from Positron-Emission-Tomography was also evaluated. RESULTS: Several variables were correlated with a diagnosis of mycobacterial infection or lung cancer on univariate analysis. Such variable include smoking status and history, lesion size and imaging evidence of tree-in-bud opacities, lymphadenopathy or emphysema on computed tomography. Upon author consensus, the most clinically-relevant variables were selected to undergo multivariate analysis. A history of current or former smoking [OR 4.4 (95 % CI 1.2-15.6) and 2.7 (95 % CI 1.1-6.8), respectively P = 0.04] was correlated with diagnoses of lung cancer. Contrarily, the presence of tree-in-bud opacities was less likely to be correlated with a diagnosis of malignancy [OR 0.04 (95 % CI 0.0-1.0), P = 0.05]. Additionally, higher maximum standardized uptake values from positron emission tomography were associated with malignancy on multivariate analysis [OR 1.1 (95 % CI 1.0-1.2), P = 0.04]; but the accuracy of the values in differentiating between diseases was only 0.67 as measured by the area under the curve. Lesion size was not independently associated with diagnosis [OR 0.5 (95 % CI 0.2-1.2), (P = 0.12)]. CONCLUSIONS: Establishing the likelihood of malignancy for lung nodules based on isolated clinical or radiographic criteria is difficult. Using the variables found in this study may allow clinicians to stratify patients into groups of high and low risk for malignancy, and therefore establish efficient diagnostic strategies.

Ribosomal RNA gene sequencing for early diagnosis of Blastomyces dermatitidis infection.

Prompt detection and identification of fungal pathogens at the genus and species level is critical in order to provide timely antifungal therapy. Here, we highlight the vital role of molecular diagnostics in achieving a fast and definitive diagnosis of disseminated blastomycosis in a diabetic patient presenting as a brain mass initially thought to be tumoral in nature. A broad-range PCR amplification and sequencing of the fungal ribosomal RNA genes on brain biopsy tissue obtained during elective craniotomy revealed a final microbial identification of Ajellomyces dermatitidis (telemorph of Blastomyces dermatitidis).

Infectious atherosclerosis: is the hypothesis still alive? A clinically based approach to the dilemma.

Among the multiple factors involved in the pathophysiology of heart disease, infections have been proposed to play a role in atherosclerosis with most of the available evidence implicating Chlamydia pneumonia, influenza virus and Mycoplasma pneumoniae. Based on a model case presentation, we speculate that in the absence of traditional risk factors and in the context of an ongoing respiratory infection caused by a pro-inflammatory pathogen (M. pneumoniae) along with a past positive serologic history for potentially proven atherogenic microorganism (C. pneumoniae) and infection may elicit potentially pathogenic events on vascular wall cells and leukocytes of atheromatous lesions, supporting the hypothesis that such infections may potentiate atherosclerotic cardiovascular disease (CVD).