Pathogens and Immunity最新文献

Background: Two novel malaria vaccines, RTS,S and R21, mark a significant step forward in malaria research, but eradication demands vaccines with higher efficacy. Recent trials using late-arresting genetically attenuated parasites (LA-GAP) highlight their effectiveness as next-generation vaccines, likely through CD8⁺ T-cell activation targeting late liver-stage parasites. However, the distribution of LA-GAP-activated T cells in different organs that culminate towards high-level protection in the liver remains unclear.

Methods: This study aimed to map immune responses in the livers and lungs of mice immunized with LA-GAP, shedding light on the role of different organs in priming T-cell responses towards immunity.

Results: Particularly in the lungs we found an impressive increase of CD8⁺, double negative T cells (5%), γδ (2.5%), effector memory CD8⁺ T cells (46%), and tissue resident memory CD8⁺ T cells (3%). These lung T cells are highly activated (expressing CD11c, Ki67, KLRG1) and exhibited 4-fold higher Granzyme A expression and significant TNF⁺ cell increases as compared to their liver counterparts (10.2% vs 2.6%). These differences start already at the early 2-day timepoint at which time the lungs show an impressive 10.2% increase in TNF⁺ CD8⁺ T cells, whereas the liver shows a more modest increase of 2.6% of these cells.

Conclusion: These findings highlight the lungs as a crucial site for immune priming and T-cell activation, underscoring the need for further investigation of organ-specific responses to fully understand the potential of LA-GAP immunization as a powerful strategy in the fight against malaria.

Background: In the field of tuberculosis and non-tuberculous mycobacterial (NTM) disease we are looking back on an exciting year 2024 with more than 10,000 publications listed in PubMed.

Methods: Our aim, to review the scientific literature of the year 2024, is challenged by the enormous number of publications. Therefore, if your article is not included or your favorite field of mycobacteriology not covered, please forgive us. Our "Year in Review" is very much clinically oriented with lesser emphasis on basic science, microbiology, and biotechnology.

Results: Members of the steering committee of the Tuberculosis Network European Trials group (TBnet; www.tbnet.eu) report on 139 publications in the fields of epidemiology, prevention, diagnosis, and treatment of tuberculosis and NTM diseases published in 2024 that we found particularly important. We report publications separately for tuberculosis in children and adults and for NTM disease and provide a brief overview of newer technologies in the diagnostic pipeline. Furthermore, we summarize priorities for tuberculosis and NTM disease research, development, and implementation, all of which represent the perspective of our combined clinical experience.

Conclusions: This Year in Review provides a concise summary of the clinically relevant highlights of the published literature in tuberculosis and NTM diseases in 2024.

The science of extracellular vesicles (EVs) is a rapidly growing field that spans multiple aspects of normal physiology and pathophysiology. EVs play a critical role in most basic biological processes of cell-cell communications under normal conditions and in disease. EVs have "gone viral" not only in terms of research popularity, but also in our realization that they exhibit an elaborate crosstalk with viruses, particularly with the enveloped ones, which are also extracellular vesicles that are released by cells as a part of their virulence cycle yet are replicative. Here, we highlight some of the complexities underlying EV-virus crosstalk and pathways and provide our insights on key challenges from the viewpoint of EV biology.

Background: A detailed understanding of the human antibody response to outer surface protein C (OspC) of Borrelia burgdorferi has important implications for Lyme disease diagnostics and vaccines.

Methods: In this report, 13 peptides encompassing 8 reported OspC linear B-cell epitopes from OspC types A, B, and K, including the largely conserved C-terminus (residues 193-210), were evaluated by multiplex immunoassay (MIA) for IgG reactivity with ~700 human serum samples confirmed positive in a 2-tiered Lyme disease diagnostic assay (Bb⁺) and ~160 post-treatment Lyme disease (PTLD) serum samples. The vmp-like sequence E (VlsE) C6-17 peptide was included as a positive control.

Results: Serum IgG from Bb⁺ samples were reactive with 10 of the 13 OspC-derived peptides tested, with the C-terminal peptide (residues 193-210) being the most reactive. Spearman's rank correlation matrices and hierarchical clustering revealed a strong correlation between 193-210 and VlsE C6-17 peptide reactivity but little demonstrable association between 193-210 and the other OspC peptides or recombinant OspC. OspC peptide reactivities (excluding 193-210) were strongly correlated with each other and were disproportionately influenced by a subset of pan-reactive samples. In the PTLD sample set, none of the OspC-derived peptides were significantly reactive over baseline, even though VlsE C6-17 peptide reactivity remained.

Conclusions: The asynchronous and potentially short-lived serologic response to OspC-derived peptides reveals the complexity of B-cell responses to B. burgdorferi lipoproteins and confounds interpretation of antibody profiles for Lyme disease diagnostics.

Background: Human herpesvirus-8 (HHV-8), or Kaposi sarcoma (KS)-associated herpesvirus (KSHV), causes severe disease in people with profound immunosuppression. Yet, diagnosing KS can be challenging given the diverse manifestations and current limited usual care diagnostic methods (UC; polymerase chain reaction, histopathology).

Methods: Pathogen-agnostic plasma microbial cell-free DNA sequencing was applied to banked samples from 116 outpatients included in 2 previous prospective studies of patients with antiretroviral treatment-naïve, advanced HIV (CD4 count ≤100 cells/μL). We then reviewed clinical and laboratory data for any people who tested positive for HHV-8 by mcfDNA sequencing or UC at baseline.

Results: HHV-8 was detected in 21 (18%) outpatients with advanced HIV by any method, with males comprising the majority (86%) and one-third originally from non-US countries (including Africa, Central America, and the Caribbean). Adding mcfDNA sequencing to UC proportionally increased HHV-8 detection by 38%, while also identifying in 18 (86%) people other microbes of potential interest, including common herpesviruses, Mycobacterium tuberculosis, and Pneumocystis jirovecii.

Conclusions: Plasma mcfDNA sequencing may improve UC in detection of HHV-8 infection, especially in immunocompromised outpatients, in whom early detection may facilitate appropriate management to prevent severe KS disease. The potential added benefit of the detection of other pathogens by mcfDNA sequencing may be particularly relevant for this population.

Rationale: Treatment monitoring of tuberculosis patients is complicated by a slow growth rate of Mycobacterium tuberculosis. Recently, host RNA signatures have been used to monitor the response to tuberculosis treatment.

Objective: Identifying and validating a whole blood-based RNA signature model to predict microbiological treatment responses in patients on tuberculosis therapy.

Methods: Using a multi-step machine learning algorithm to identify an RNA-based algorithm to predict the remaining time to culture conversion at flexible time points during anti-tuberculosis therapy.

Results: The identification cohort included 149 patients split into a training and a test cohort, to develop a multistep algorithm consisting of 27 genes (TB27) for predicting the remaining time to culture conversion (TCC) at any given time. In the test dataset, predicted TCC and observed TCC achieved a correlation coefficient of r=0.98. An external validation cohort of 34 patients shows a correlation between predicted and observed days to TCC also of r=0.98.

Conclusion: We identified and validated a whole blood-based RNA signature (TB27) that demonstrates an excellent agreement between predicted and observed times to M. tuberculosis culture conversion during tuberculosis therapy. TB27 is a potential useful biomarker for anti-tuberculosis drug development and for prediction of treatment responses in clinical practice.

Klebsiella pneumoniae (Kp) is a Gram-negative pathogen responsible for both hospital- and community-acquired infections. Kp is classified into 2 distinct pathotypes: classical K. pneumoniae (cKp) and hypervirulent K. pneumoniae (hvKp). First described in Taiwan in 1986, hvKp are highly pathogenic and characterized by unique phenotypic and genotypic traits. The hypermucoviscous (hmv) phenotype, generally marked by overproduction of the capsule, is often associated with hvKp, although recent studies show that some cKp strains may also have this characteristic. Furthermore, hvKp can cause severe community-acquired infections in healthy people and have been associated with metastatic infections such as liver abscess, meningitis, and endophthalmitis. HvKp are increasingly being reported in hospital-acquired settings, complicating treatment strategies. In particular, while hvKp have historically been antibiotic-susceptible, multidrug-resistant (MDR) strains have emerged and pose a significant public health threat. The combination of high virulence and limited antibiotic options demands further research into virulence mechanisms and rapid identification methods. This review discusses the epidemiology of hvKp and their virulence factors, highlighting the importance of phenotypic and non-phenotypic tests, including next-generation molecular diagnostics, for the early detection of hvKp.

Background: Antibody-dependent cell-mediated cytotoxic (ADCC) response mediated by natural killer (NK) cells correlates with decreased infection risk in studies involving simian immunodeficiency virus (SIV)/simian-human immunodeficiency virus (SHIV), and human immunodeficiency virus (HIV) vaccine candidates. Currently, the heterogeneities of the functional subset of rhesus macaque natural killer (RMNK) cells are under-characterized.

Method: We engaged the RMNK cells with ADCC-mediating anti-HIV-1 monoclonal antibodies (ADCCAbs) or anti-CD16 antibodies and used CD107a expression as the surrogate marker for RMNK cells actively involved in ADCC. CD107a⁺ and CD107a^- populations were analyzed individually using single-cell RNA sequencing.

Results: Subsets of CD107a⁺ RMNK cells produced more chemokines than the others, suggesting that these cells not only eliminate infected cells but also provide immunoregulatory signals and potentially curb HIV-1 replication. Crosslinking of Fc gamma receptor IIIa via anti-CD16 antibodies resulted in a significantly higher percentage of degranulating cells than via ADCCAbs. However, the magnitude of degranulation and chemokine production was reduced by 6- to 30-fold.

Conclusion: The quality and quantity of receptor engagement are important determinants of achieving an optimal level of the RMNK response.

Background: Optimal control of microbial infections requires mucosal-associated invariant T (MAIT) cells. People living with HIV (PWH) on antiretroviral therapy (ART) can be divided into 2 groups: immune responders (IR) who recover or retain CD4 T cell numbers, and immune non-responders (INR) who do not. Compared to IR, INR have fewer MAIT cells and increased systemic inflammation and microbial translocation, but how these factors affect MAIT cells is unknown.

Methods: MAIT cells from IR, INR, and from controls without HIV were enumerated and characterized by flow cytometry. To determine the links among MAIT cells, inflammation, and microbial translocation, the correlations of MAIT cell numbers to previously published soluble inflammatory markers and plasma microbial genetic sequences were assessed by Spearman analysis. In vitro assays were used to support our findings.

Results: MAIT cell numbers were significantly negatively correlated with levels of IL-6 and IP-10 (markers of inflammation); CD14, LPS, and FABP2 (markers of microbial translocation); and with abundance of Serratia and other Proteobacteria genetic sequences in plasma. In a separate analysis of PWH on ART receiving the IL-6 receptor antagonist tocilizumab (TCZ), we found that blocking IL-6 signaling with TCZ increased IL-7 receptor expression on MAIT cells and reduced plasma IL-7 levels, consistent with improved uptake of IL-7 in vivo.

Conclusions: Our findings suggest inflammation and microbial translocation in PWH on ART lead to a loss of MAIT cells via impaired IL-7 responsiveness, resulting in further increased microbial translocation and inflammation.