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The gut microbiota contributes to maintaining human health and regulating immune responses. Severe COVID-19 illness is associated with a dysregulated pro-inflammatory immune response. The effect of SARS-CoV-2 on altering the gut microbiome and the relevance of the gut microbiome on COVID-19 severity needs to be clarified. In this prospective study, we analyzed the gut microbiome of 212 patients of a tertiary care hospital (117 patients infected with SARS-CoV-2 and 95 SARS-CoV-2 negative patients) using 16S rRNA gene sequencing of the V3-V4 region. Inflammatory markers and immune cells were quantified from blood. The gut microbiome in SARS-CoV-2 infected patients was characterized by a lower bacterial richness and distinct differences in the gut microbiome composition, including an enrichment of the phyla Proteobacteria and Bacteroidetes and a decrease of Actinobacteria compared to SARS-CoV-2 negative patients. The relative abundance of several genera including Bifidobacterium , Streptococcus and Collinsella was lower in SARS-CoV-2 positive patients while the abundance of Bacteroides and Enterobacteriaceae was increased. Higher pro-inflammatory blood markers and a lower CD8 + T cell number characterized patients with severe COVID-19 illness. The gut microbiome of patients with severe/critical COVID-19 exhibited a lower abundance of butyrate-producing genera Faecalibacterium and Roseburia and a reduction in the connectivity of a distinct network of anti-inflammatory genera that was observed in patients with mild COVID-19 illness and in SARS-CoV-2 negative patients. Dysbiosis of the gut microbiome associated with a pro-inflammatory signature may contribute to the hyperinflammatory immune response characterizing severe COVID-19 illness.

Despite advancements in cancer therapies, bacterial complications remain a major challenge, delaying treatment and worsening outcomes. While immunosuppressive therapies and prolonged hospitalizations contribute, they do not fully explain the elevated infection risk in cancer patients. Here we show that tumors producing high levels of granulocyte colony-stimulating factor (G-CSF) promote the persistence of Gram-negative pathogens in head and neck squamous cell carcinoma due to neutrophil reprogramming. Mechanistically, we identify tumor-driven activation of the G-CSF / nicotinamide phosphoribosyltransferase (NAMPT) signaling axis in neutrophil progenitors, resulting in impaired antibacterial functions, such as phagocytosis and neutrophil extracellular traps formation, and development of tissue-damaging neutrophil subsets. This disrupts lung tissue integrity and facilitates bacterial persistence. Importantly, targeting the G-CSF/NAMPT pathway prevents the generation of dysfunctional neutrophils and improves bacterial clearance in vivo. Our findings reveal tumor-induced, NAMPT-dependent neutrophil reprogramming as a central driver of compromised antimicrobial defenses in cancer. Therapeutic strategies aimed at modulating G-CSF/NAMPT signaling could enhance infection control and survival for cancer patients. Cancer patients are at increased risk for severe bacterial infections due to immune dysfunction. Here, the authors show that chronic tumor-derived G-CSF drives NAMPT/NAD-dependent neutrophil dysfunction from the progenitor stage, and that targeting this pathway restores infection control.

Background Mycobacterium (M.) chimaera is a non-tuberculous mycobacterium (NTM) that belongs to M. avium complex (MAC). In patients with cystic fibrosis (CF), MAC can cause bronchopulmonary infections that can be prolonged and difficult to treat. MAC infections of sites other than the lungs or central catheters are rare and almost exclusively associated with immunodeficiency. Case presentation We present a case of an 8-year-old CF patient (delF508 homozygous) with recurrent pulmonary exacerbations, gradual clinical deterioration, B-symptoms (fever, fatigue, weight loss, night sweat), elevated transaminases and intermittent detection of M. chimaera in the sputum without radiological signs of NTM-associated lung disease with a central venous port-catheter. Next-generation sequencing (NGS) revealed M. chimaera port infection that was also confirmed by mycobacterial culture. The patient recovered within 4 weeks after removal of the catheter and initiation of MAC targeted antimicrobial therapy. Electron microscopy of the catheter illustrated the presence of mycobacteria in a biofilm. Conclusions MAC central venous catheter infection needs to be considered in immunocompetent people. NGS is a valuable tool for rapid identification of rare infections. MAC capability of biofilm formation renders catheter removal the central therapeutic intervention for the clearance of the infection.

Background The Mycobacterium avium complex (MAC) comprises the most frequent non-tuberculous mycobacteria (NTM) in Central Europe and currently includes twelve species. M. avium (MAV), M. intracellulare subsp. intracellulare (MINT), and M. intracellulare subsp. chimaera (MCH) are clinically most relevant. However, the population structure and genomic landscape of MAC linked with potential pathobiological differences remain little investigated. Methods Whole genome sequencing (WGS) was performed on a multi-national set of MAC isolates from Germany, France, and Switzerland. Phylogenetic analysis was conducted, as well as plasmids, resistance, and virulence genes predicted from WGS data. Data was set into a global context with publicly available sequences. Finally, detailed clinical characteristics were associated with genomic data in a subset of the cohort. Results Overall, 610 isolates from 465 patients were included. The majority could be assigned to MAV ( n  = 386), MCH ( n  = 111), and MINT ( n  = 77). We demonstrate clustering with less than 12 SNPs distance of isolates obtained from different patients in all major MAC species and the identification of trans-European or even trans-continental clusters when set into relation with 1307 public sequences. However, none of our MCH isolates clustered closely with the heater-cooler unit outbreak strain Zuerich-1. Known plasmids were detected in MAV (325/1076, 30.2%), MINT (62/327, 19.0%), and almost all MCH-isolates (457/463, 98.7%). Predicted resistance to aminoglycosides or macrolides was rare. Overall, there was no direct link between phylogenomic grouping and clinical manifestations, but MCH and MINT were rarely found in patients with extra-pulmonary disease (OR 0.12 95% CI 0.04–0.28, p  < 0.001 and OR 0.11 95% CI 0.02–0.4, p  = 0.004, respectively) and MCH was negatively associated with fulfillment of the ATS criteria when isolated from respiratory samples (OR 0.28 95% CI 0.09-0.7, p = 0.011). With 14 out of 43 patients with available serial isolates, co-infections or co-colonizations with different strains or even species of the MAC were frequent (32.6%). Conclusions This study demonstrates clustering and the presence of plasmids in a large proportion of MAC isolates in Europe and in a global context. Future studies need to urgently define potential ways of transmission of MAC isolates and the potential involvement of plasmids in virulence.

Abstract Background Human immunodeficiency virus (HIV) infection is an independent risk factor for coronary heart disease (CHD) and is associated with perturbation of the gut microbiota. Methods We analyzed gut microbiota in 30 HIV-infected individuals with CHD (CHD+) and 30 without CHD (CHD–) of the HIV-HEART study group. Results Gut microbiota linked to CHD was associated with lower α-diversity. Despite insignificant differences in β-diversity, co-occurrence networks of bacterial genera clearly diverged between CHD+ and CHD– individuals. Multidimensional scaling separated HIV-infected individuals into 2 microbiome clusters, dominated by the genus Prevotella or Bacteroides. The relative abundance of 49 other genera was significantly different between both clusters. The Prevotella-rich cluster was largely composed of men who have sex with men (MSM) (97%), whereas the Bacteroides-rich cluster comprised both MSM (45%) and heterosexual individuals (55%). MSM of the Bacteroides-rich cluster were characterized by reduced α-diversity, advanced immunological HIV stage, longer antiretroviral therapy with more ART regimens, and longer use of protease inhibitors, compared with Prevotella-rich MSM. Conclusions Community structures of gut microbiota rather than individual species might facilitate risk assessment of CHD in HIV-infected individuals. Sexual behavior appears to be an important factor affecting gut microbiota β-diversity and should be considered in future studies. Gut microbiota linked to coronary heart disease in HIV infection is characterized by reduced α-diversity and altered co-occurrence network despite insignificant differences in β-diversity. Sexual behavior affects β-diversity of the gut microbiota and should be considered in future studies.

Clinical and experimental studies indicate that the bacterial and fungal gut microbiota modulates immune responses in distant organs including the lungs. Immune dysregulation is associated with severe SARS-CoV-2 infection, and several groups have observed gut bacterial dysbiosis in SARS-CoV-2 infected patients, while the fungal gut microbiota remains poorly defined in these patients. We analyzed the fungal gut microbiome from rectal swabs taken prior to anti-infective treatment in 30 SARS-CoV-2 positive (21 non-severe COVID-19 and 9 developing severe/critical COVID-19 patients) and 23 SARS-CoV-2 negative patients by ITS2-sequencing. Pronounced but distinct interconnected fungal communities distinguished SARS-CoV-2 positive and negative patients. Fungal gut microbiota in severe/critical COVID-19 illness was characterized by a reduced diversity, richness and evenness and by an increase of the relative abundance of the Ascomycota phylum compared with non-severe COVID-19 illness. A dominance of a single fungal species with a relative abundance of >75% was a frequent feature in severe/critical COVID-19. The dominating fungal species were highly variable between patients even within the groups. Several fungal taxa were depleted in patients with severe/critical COVID-19.The distinct compositional changes of the fungal gut microbiome in SARS-CoV-2 infection, especially in severe COVID-19 illness, illuminate the necessity of a broader approach to investigate whether the differences in the fungal gut microbiome are consequences of SARS-CoV-2 infection or a predisposing factor for critical illness.

Marmots are an important reservoir of Yersinia pestis and a source of human plague in Mongolia. We present two fatal cases of plague after consumption of raw marmot organs and discuss the distribution of natural foci of Y. pestis in Mongolia.

Background The discrimination of the members of the Mycobacterium abscessus complex is of clinical interest because one of the subspecies, M. massiliense, exhibits higher rates of response to antibiotic treatment for lung infection than do the other members of that complex. M. abscessus complex contains three subspecies that are laborious to identify; therefore, a routine diagnostic tool would be worthwhile. Results We used principal component analysis, hierarchical cluster analysis, and single-peak analysis to examine peak lists derived from matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI TOF MS) mass spectra of 50 clinical M. abscessus complex isolates, including 28  M. abscessus (sensu stricto) , 19  M. massiliense, and 3  M. bolletii isolates grown in mycobacterium growth indicator tube liquid medium and prepared with a bead-based protocol. Principal component analysis but not hierarchical cluster analysis separated M. abscessus (sensu stricto) isolates and M. massiliense isolates into two clusters. Furthermore, single-peak analysis displayed 4 discriminating peaks that separated M. abscessus (sensu stricto) from M. massiliense isolates. M. bolletii isolates did not exhibit specific peaks but resembled the M. abscessus (sensu stricto) peak profile and also grouped within this principal component analysis cluster. Principal component analysis of all peak lists with the exclusion of the four discriminating peaks again separated M. abscessus (sensu stricto) from M. massiliense isolates, thus relativizing the importance of these peaks for subspecies identification. Conclusions Principal component analysis of peak lists derived from MALDI TOF mass spectra is a robust and convenient method of discriminating M. massiliense isolates from the other members of the M. abscessus complex.

Specific antiretroviral therapy (ART) regimens are associated with weight gain in people living with HIV (PLWH). Gut microbiota is involved in weight gain in humans and animals. Human gut microbiota can be classified into enterotypes with distinct microbial and functional profiles. In a cohort of 118 PLWH, we analyzed the gut microbiome in relation to weight gain and ART regimen using gene sequencing, taking enterotype classification into account. The enterotype was strongly associated with sexual orientation. Of the 67 individuals forming a -dominated enterotype cluster in principal coordinates analysis, 93% were men who had sex with men (MSM), while 31% of individuals in the -dominated enterotype cluster were MSM and 69% were non-MSM. Forty-nine genera differed significantly between the MSM and non-MSM individuals. When stratified by dominant genus, only six taxa were associated with weight gain. Of these, five were restricted to -dominated individuals. Among them, the class Actinobacteria and genus differed between individuals gaining more than 5% weight and less than 5% weight 1 year after ART switch. Additionally, three taxa were significantly different between 15% of individuals with the highest weight gain (≥6.3%) and the highest weight loss (≤3.19%) 1 year after ART switch, including the phyla Firmicutes, Verrucomicrobia, and Synergistetes. Distinct functional properties in , but not -dominated enterotype individuals, linked to weight gain were observed, particularly for glycan and lipid metabolism. Additionally, ART regimen-associated differences were observed for the phylum Actinobacteria, although this was limited to dominated enterotype individuals. Differences in the composition and functional characteristics of the gut microbiome associated with weight gain and ART regimens were enterotype-specific and relatively small compared with differences linked to sexual orientation. Due to the substantial differences in gut microbiome structure among many MSM, categorization into enterotypes is useful for identifying differences in microbiome composition associated with variables such as weight gain or ART, which may be limited to a single enterotype. This may further advance the identification of microbes that contribute to weight gain or alter the gut microbiome composition in the context of the enterotype.

During sepsis, a relative increase of regulatory T (Treg) cells has been reported. Its persistence is associated with lymphocyte anergy, immunoparalysis and a poor prognosis. Currently, an exact quantification of human Treg cells based on protein expression of marker molecules is ambiguous, as these molecules are expressed also by activated non-regulatory T cells. Furthermore, no firm criteria for flow cytometer gate settings exist so far. Recently, a specific DNA methylation pattern within FOXP3-TSDR has been reported that allows distinguishing Treg and non-regulatory T cells, independent of their activation status. Using this epigenetic marker, we established a single-tube real-time PCR based methylation assay (QAMA) for relative quantification of Treg cells. Validation was performed on defined ratios of methylated and unmethylated target sequence and on mixtures of Treg and non-regulatory T cells. DNA-methylation was measured in CD4(+) T cells isolated from blood samples of 30 septic patients and 30 healthy subjects and compared with results of Treg cell quantification by flow cytometry based on CD4(+) CD25(hi)CD127(low) measurement. In septic patients both methods showed an increased ratio of Treg cells to all CD4(+) T cells. In healthy individuals, the results obtained by both methods were clearly positively correlated. However, the correlation between both methods in septic patients was only weak. We showed that quantification of Treg cells by QAMA detects CD4(+) T cells with unmethylated FOXP3-TSDR, hidden in the CD25(med/low) fraction of flow cytometry. Given that unmethylated FOXP3-TSDR is the most specific feature of Treg cells to date, our assay precisely quantifies Treg cells, as it additionally detects those committed Treg cells, hidden in the CD25(med/low) fraction of CD4(+) cells. Furthermore, QAMA is a reliable method, which is easier to standardize among laboratories and can thus improve reproducibility of Treg cell quantification.