Exposure to Mycobacterium remodels alveolar macrophages and the early innate response to Mycobacterium tuberculosis infection.

Alveolar macrophages (AMs) play a critical role during Mycobacterium tuberculosis (Mtb) infection as the first cells in the lung to encounter bacteria. We previously showed that AMs initially respond to Mtb in vivo by mounting a cell-protective, rather than pro-inflammatory response. However, the plasticity of the initial AM response was unknown. Here, we characterize how previous exposure to Mycobacterium, either through subcutaneous vaccination with Mycobacterium bovis (scBCG) or through a contained Mtb infection (coMtb) that mimics aspects of concomitant immunity, impacts the initial response by AMs. We find that both scBCG and coMtb accelerate early innate cell activation and recruitment and generate a stronger pro-inflammatory response to Mtb in vivo by AMs. Within the lung environment, AMs from scBCG vaccinated mice mount a robust interferon-associated response, while AMs from coMtb mice produce a broader inflammatory response that is not dominated by Interferon Stimulated Genes. Using scRNAseq, we identify changes to the frequency and phenotype of airway-resident macrophages following Mycobacterium exposure, with enrichment for both interferon-associated and pro-inflammatory populations of AMs. In contrast, minimal changes were found for airway-resident T cells and dendritic cells after exposures. Ex vivo stimulation of AMs with Pam3Cys, LPS and Mtb reveal that scBCG and coMtb exposures generate stronger interferon-associated responses to LPS and Mtb that are cell-intrinsic changes. However, AM profiles that were unique to each exposure modality following Mtb infection in vivo are dependent on the lung environment and do not emerge following ex vivo stimulation. Overall, our studies reveal significant and durable remodeling of AMs following exposure to Mycobacterium, with evidence for both AM-intrinsic changes and contributions from the altered lung microenvironments. Comparisons between the scBCG and coMtb models highlight the plasticity of AMs in the airway and opportunities to target their function through vaccination or host-directed therapies.

Mycobacterium tuberculosis infection associated immune perturbations correlate with antiretroviral immunity.

Infection with Mycobacterium tuberculosis (MTB) remains one of the most important opportunistic infections in people with HIV-1 (PWH). While active Tuberculosis (TB) leads to rapid progression of immunodeficiency in PWH, the interaction between MTB and HIV-1 during the asymptomatic phase of both infections remains poorly understood. In a cohort of individuals with HIV (PWH) with and without suppressed HIV-1 viral load, the transcriptomic profiles of peripheral blood mononuclear cells (PBMC) clustered in individuals infected with Mycobacterium tuberculosis (MTB) compared to carefully matched controls. Subsequent functional annotation analysis disclosed alterations in the IL-6, TNF, and KRAS pathways. Notably, MTB-associated genes demonstrated an inverse correlation with HIV-1 viremia, evident at both on individual gene level and when employed as a gene score. In sum, our data show that MTB infection in PWH is associated with a shift in the activation state of the immune system, displaying an inverse relationship with HIV-1 viral load. These results could provide an explanation for the observed increased antiretroviral control associated with MTB infection in PWH.

Understanding the Decline of Incident, Active Tuberculosis in People With Human Immunodeficiency Virus in Switzerland.

BACKGROUND: People with human immunodeficiency virus type 1 (HIV-1) (PWH) are frequently coinfected with Mycobacterium tuberculosis (MTB) and at risk for progressing from asymptomatic latent TB infection (LTBI) to active tuberculosis (TB). LTBI testing and preventive treatment (TB specific prevention) are recommended, but its efficacy in low transmission settings is unclear. METHODS: We included PWH enrolled from 1988 to 2022 in the Swiss HIV Cohort study (SHCS). The outcome, incident TB, was defined as TB ≥6 months after SHCS inclusion. We assessed its risk factors using a time-updated hazard regression, modeled the potential impact of modifiable factors on TB incidence, performed mediation analysis to assess underlying causes of time trends, and evaluated preventive measures. RESULTS: In 21 528 PWH, LTBI prevalence declined from 15.1% in 2001% to 4.6% in 2021. Incident TB declined from 90.8 cases/1000 person-years in 1989 to 0.1 in 2021. A positive LTBI test showed a higher risk for incident TB (hazard ratio [HR] 9.8, 5.8-16.5) but only 10.5% of PWH with incident TB were tested positive. Preventive treatment reduced the risk in LTBI test positive PWH for active TB (relative risk reduction, 28.1%, absolute risk reduction 0.9%). On population level, the increase of CD4 T-cells and reduction of HIV viral load were the main driver of TB decrease. CONCLUSIONS: TB specific prevention is effective in selected patient groups. On a population level, control of HIV-1 remains the most important factor for incident TB reduction. Accurate identification of PWH at highest risk for TB is an unmet clinical need.

[Clinical presentation and Treatment of Lyme Disease]. / Klinik und Therapie der Lyme-Borreliose.

Clinical presentation and Treatment of Lyme Disease Abstract. Lyme borreliosis is a tick-born disease caused by Borrelia burgdorferi sensu lato characteristically occurring in the northern hemisphere. Typically, the first manifestation is a localized infection of the skin with an expanding rash, commonly referred to as Erythema migrans. Early disseminated infections typically affect the central nervous system and, less commonly, the heart causing carditis. Late manifestations include arthritis and skin involvement, the so called "Acrodermatitis atrophicans". However, the chronology of signs and symptoms is not a necessity: late manifestations of the disease might also present as the first symptoms and need to be considered accordingly. With the exemption of Erythema migrans, which does not require serology, the diagnosis of infection with Borrelia relies on a synthesis of signs and symptoms and a positive serology. Infection with Borrelia can be treated with appropriate antibiotic regimens, especially beta-lactam derivatives and tetracyclines. Despite successful treatment, post-infectious symptoms may develop in a fraction of patients.

Monkeypox Virus Infection in Humans across 16 Countries - April-June 2022.

BACKGROUND: Before April 2022, monkeypox virus infection in humans was seldom reported outside African regions where it is endemic. Currently, cases are occurring worldwide. Transmission, risk factors, clinical presentation, and outcomes of infection are poorly defined. METHODS: We formed an international collaborative group of clinicians who contributed to an international case series to describe the presentation, clinical course, and outcomes of polymerase-chain-reaction-confirmed monkeypox virus infections. RESULTS: We report 528 infections diagnosed between April 27 and June 24, 2022, at 43 sites in 16 countries. Overall, 98% of the persons with infection were gay or bisexual men, 75% were White, and 41% had human immunodeficiency virus infection; the median age was 38 years. Transmission was suspected to have occurred through sexual activity in 95% of the persons with infection. In this case series, 95% of the persons presented with a rash (with 64% having ≤10 lesions), 73% had anogenital lesions, and 41% had mucosal lesions (with 54 having a single genital lesion). Common systemic features preceding the rash included fever (62%), lethargy (41%), myalgia (31%), and headache (27%); lymphadenopathy was also common (reported in 56%). Concomitant sexually transmitted infections were reported in 109 of 377 persons (29%) who were tested. Among the 23 persons with a clear exposure history, the median incubation period was 7 days (range, 3 to 20). Monkeypox virus DNA was detected in 29 of the 32 persons in whom seminal fluid was analyzed. Antiviral treatment was given to 5% of the persons overall, and 70 (13%) were hospitalized; the reasons for hospitalization were pain management, mostly for severe anorectal pain (21 persons); soft-tissue superinfection (18); pharyngitis limiting oral intake (5); eye lesions (2); acute kidney injury (2); myocarditis (2); and infection-control purposes (13). No deaths were reported. CONCLUSIONS: In this case series, monkeypox manifested with a variety of dermatologic and systemic clinical findings. The simultaneous identification of cases outside areas where monkeypox has traditionally been endemic highlights the need for rapid identification and diagnosis of cases to contain further community spread.

Impact of Latent Tuberculosis on Diabetes.

While an increased risk of active and latent tuberculosis infection (LTBI) in people with type-2 diabetes (DM) has been demonstrated, it is less well characterized whether LTBI is associated with an increased risk of developing DM. We investigated the link between LTBI and DM in people living with HIV in the Swiss HIV Cohort Study via time-dependent Cox proportional hazards models. We found that LTBI significantly increased the risk of developing DM (HR = 1.47), which was robust across different adjustment and censoring techniques. Our results thus suggest that LTBI may be associated with an increased risk of developing DM.

Use of a Contained Mycobacterium tuberculosis Mouse Infection Model to Predict Active Disease and Containment in Humans.

Previous studies have identified whole-blood transcriptional risk and disease signatures for tuberculosis; however, several lines of evidence suggest that these signatures primarily reflect bacterial burden, which increases before symptomatic disease. We found that the peripheral blood transcriptome of mice with contained Mycobacterium tuberculosis infection (CMTI) has striking similarities to that of humans with active tuberculosis and that a signature derived from these mice predicts human disease with accuracy comparable to that of signatures derived directly from humans. A set of genes associated with immune defense are up-regulated in mice with CMTI but not in humans with active tuberculosis, suggesting that their up-regulation is associated with bacterial containment. A signature comprising these genes predicts both protection from tuberculosis disease and successful treatment at early time points where current signatures are not predictive. These results suggest that detailed study of the CMTI model may enable identification of biomarkers for human tuberculosis.

Disseminated Mycobacterium simiae and Mycobacterium avium infection causing an immune reconstitution inflammatory syndrome in a female patient with HIV infection.

This case study discusses the management of a disseminated Mycobacterium simiae and Mycobacterium avium infection causing an immune reconstitution inflammatory syndrome in a 52-year-old woman with HIV infection. Disseminated M. avium infections have extensively been described in HIV patients; however, reports of infections with M. simiae are rare. Treatment of M. simiae infections is challenging due to its high rates of natural drug resistances, and thus far, no standard treatment regimen exists.

HIV-Infected Patients Developing Tuberculosis Disease Show Early Changes in the Immune Response to Novel Mycobacterium tuberculosis Antigens.

Background: In individuals living with HIV infection the development of tuberculosis (TB) is associated with rapid progression from asymptomatic TB infection to active TB disease. Sputum-based diagnostic tests for TB have low sensitivity in minimal and subclinical TB precluding early diagnosis. The immune response to novel Mycobacterium tuberculosis in-vivo expressed and latency associated antigens may help to measure the early stages of infection and disease progression and thereby improve early diagnosis of active TB disease. Methods: Serial prospectively sampled cryopreserved lymphocytes from patients of the Swiss HIV Cohort Study developing TB disease ("cases") and matched patients with no TB disease ("controls") were stimulated with 10 novel Mycobacterium tuberculosis antigens. Cytokine concentrations were measured in cases and controls at four time points prior to diagnosis of TB: T1-T4 with T4 being the closest time point to diagnosis. Results: 50 samples from nine cases and nine controls were included. Median CD4 cell count at T4 was 289/ul for the TB-group and 456/ul for the control group. Viral loads were suppressed in both groups. At T4 Rv2431c-induced and Rv3614/15c-induced interferon gamma-induced protein (IP)-10 responses and Rv2031c-induced and Rv2346/Rv2347c-induced tumor necrosis factor (TNF)-α responses were significantly higher in cases compared to controls (p < 0.004). At T3 - being up to 2 years prior to TB diagnosis - Rv2031c-induced TNF-α was significantly higher in cases compared to controls (p < 0.004). Area under the receiver operating characteristics (AUROC) curves resulted in an AUC > 0.92 for all four antigen-cytokine pairs. Conclusion: The in vitro Mycobacterium tuberculosis-specific immune response in HIV-infected individuals that progress toward developing TB disease is different from those in HIV-infected individuals that do not progress to developing TB. These differences precede the clinical diagnosis of active TB up to 2 years, paving the way for the development of immune based diagnostics to predict TB disease at an early stage.

Diagnosis of latent tuberculosis infection is associated with reduced HIV viral load and lower risk for opportunistic infections in people living with HIV.

Approximately 28% of the human population have been exposed to Mycobacterium tuberculosis (MTB), with the overwhelming majority of infected individuals not developing disease (latent TB infection (LTBI)). While it is known that uncontrolled HIV infection is a major risk factor for the development of TB, the effect of underlying LTBI on HIV disease progression is less well characterized, in part because longitudinal data are lacking. We sorted all participants of the Swiss HIV Cohort Study (SHCS) with at least 1 documented MTB test into one of the 3 groups: MTB uninfected, LTBI, or active TB. To detect differences in the HIV set point viral load (SPVL), linear regression was used; the frequency of the most common opportunistic infections (OIs) in the SHCS between MTB uninfected patients, patients with LTBI, and patients with active TB were compared using logistic regression and time-to-event analyses. In adjusted models, we corrected for baseline demographic characteristics, i.e., HIV transmission risk group and gender, geographic region, year of HIV diagnosis, and CD4 nadir. A total of 13,943 SHCS patients had at least 1 MTB test documented, of whom 840 (6.0%) had LTBI and 770 (5.5%) developed active TB. Compared to MTB uninfected patients, LTBI was associated with a 0.24 decreased log HIV SPVL in the adjusted model (p < 0.0001). Patients with LTBI had lower odds of having candida stomatitis (adjusted odds ratio (OR) = 0.68, p = 0.0035) and oral hairy leukoplakia (adjusted OR = 0.67, p = 0.033) when compared to MTB uninfected patients. The association of LTBI with a reduced HIV set point virus load and fewer unrelated infections in HIV/TB coinfected patients suggests a more complex interaction between LTBI and HIV than previously assumed.

Contained Mycobacterium tuberculosis infection induces concomitant and heterologous protection.

Progress in tuberculosis vaccine development is hampered by an incomplete understanding of the immune mechanisms that protect against infection with Mycobacterium tuberculosis (Mtb), the causative agent of tuberculosis. Although the M72/ASOE1 trial yielded encouraging results (54% efficacy in subjects with prior exposure to Mtb), a highly effective vaccine against adult tuberculosis remains elusive. We show that in a mouse model, establishment of a contained and persistent yet non-pathogenic infection with Mtb ("contained Mtb infection", CMTB) rapidly and durably reduces tuberculosis disease burden after re-exposure through aerosol challenge. Protection is associated with elevated activation of alveolar macrophages, the first cells that respond to inhaled Mtb, and accelerated recruitment of Mtb-specific T cells to the lung parenchyma. Systems approaches, as well as ex vivo functional assays and in vivo infection experiments, demonstrate that CMTB reconfigures tissue resident alveolar macrophages via low grade interferon-γ exposure. These studies demonstrate that under certain circumstances, the continuous interaction of the immune system with Mtb is beneficial to the host by maintaining elevated innate immune responses.

Polymorphisms of SOCS-1 Are Associated With a Rapid HIV Progression Rate.

OBJECTIVES: Immune activation, among others driven by interferon (IFN)-α and IFN-γ activation, is a main feature of progressive HIV infection. Suppressor of cytokine signaling (SOCS) 1 and 3 are negative feedback regulators of the IFN-α and IFN-γ axis. Here, we analyzed the role of 9 single-nucleotide polymorphisms (SNPs) within SOCS-1 and SOCS-3 genes for their association with an HIV progression rate in a cohort of 318 rapid vs 376 slow progressors from the Swiss HIV Cohort Study. DESIGN AND METHODS: We analyzed 9 SNPs, which we have identified in Swiss blood donors, in a cohort of HIV-infected patients (n = 1144), which have been categorized according to the decline in CD4 T-cell counts. In all the conducted analyses, we focused on the comparison between rapid and slow progressors with regard to SNPs in SOCS-1 and SOCS-3 and with regard to haplotypes using multivariate logistic regression models. RESULTS: Three SOCS-1 SNPs (rs193779, rs33989964, and rs4780355) are associated with a risk reduction for rapid progression. Two of these SNPs, rs33989964 and rs4780355, are in strong linkage disequilibrium, forming a frequent haplotype. Homozygous carriers of this haplotype are also associated with a risk reduction for rapid progression. By contrast, the minor TT genotype of rs33977706 is associated with twice the risk for rapid progression. No associations have been observed for the 4 SOCS-3 SNPs or the major SOCS-3 haplotypes. CONCLUSIONS: Our data suggest that SNPs in SOCS-1 are associated with HIV disease progression and speak in favor that immune activation is causal for the progressive immunodeficiency.

Monotherapy versus combination therapy for multidrug-resistant Gram-negative infections: Systematic Review and Meta-Analysis.

Infections caused by carbapenemase-producing, multidrug-resistant (MDR), or extensively drug-resistant (XDR) Gram-negative bacteria constitute a major therapeutic challenge. Whether combination antibiotic therapy is superior to monotherapy remains unknown. In this systematic review and meta-analysis OVID MEDLINE, EMBASE, PubMed, The Cochrane Library, and Scopus databases were searched for randomized controlled trials (RCTs) and observational studies published by December 2016 comparing mono- with combination antibiotic therapy for infections with carbapenemase-producing, MDR, or XDR Gram-negative bacteria. Mortality and clinical cure rates served as primary and secondary outcome measures, respectively. Of 8847 initially identified studies, 53 studies - covering pneumonia (n = 10 studies), blood stream (n = 15), osteoarticular (n = 1), and mixed infections (n = 27) - were included. 41% (n = 1848) of patients underwent monotherapy, and 59% (n = 2666) combination therapy. In case series/cohort studies (n = 45) mortality was lower with combination- vs. monotherapy (RR 0.83, CI 0.73-0.93, p = 0.002, I2 = 24%). Subgroup analysis revealed lower mortality with combination therapy with at least two in-vitro active antibiotics, in blood stream infections, and carbapenemase-producing Enterobacteriaceae. No mortality difference was seen in case-control studies (n = 6) and RCTs (n = 2). Cure rates did not differ regardless of study type. The two included RCTs had a high and unknown risk of bias, respectively. 16.7% (1/6) of case-control studies and 37.8% (17/45) of cases series/cohort studies were of good quality, whereas quality was poor in the remaining studies. In conclusion, combination antimicrobial therapy of multidrug-resistant Gram-negative bacteria appears to be superior to monotherapy with regard to mortality.

Alveolar macrophages generate a noncanonical NRF2-driven transcriptional response to Mycobacterium tuberculosis in vivo.

Alveolar macrophages (AMs) are the first cells to be infected during Mycobacterium tuberculosis (M.tb.) infection. Thus, the AM response to infection is the first of many steps leading to initiation of the adaptive immune response required for efficient control of infection. A hallmark of M.tb. infection is the slow initiation of the adaptive response, yet the mechanisms responsible for this are largely unknown. To study the initial AM response to infection, we developed a system to identify, sort, and analyze M.tb.-infected AMs from the lung within the first 10 days of infection. In contrast to what has been previously described using in vitro systems, M.tb.-infected AMs up-regulate a cell-protective antioxidant transcriptional signature that is dependent on the lung environment but not bacterial virulence. Computational approaches including pathway analysis and transcription factor motif enrichment analysis identify NRF2 as a master regulator of the response. Using knockout mouse models, we demonstrate that NRF2 drives expression of the cell-protective signature in AMs and impairs the control of early bacterial growth. AMs up-regulate a substantial pro-inflammatory response to M.tb. infection only 10 days after infection, yet comparisons with bystander AMs from the same infected animals demonstrate that M.tb.-infected AMs generate a less robust inflammatory response than the uninfected cells around them. Our findings demonstrate that the initial macrophage response to M.tb. in the lung is far less inflammatory than has previously been described by in vitro systems and may impede the overall host response to infection.

In Vivo and in Vitro Proteome Analysis of Human Immunodeficiency Virus (HIV)-1-infected, Human CD4+ T Cells.

Host-directed therapies against HIV-1 are thought to be critical for long term containment of the HIV-1 pandemic but remain elusive. Because HIV-1 infects and manipulates important effectors of both the innate and adaptive immune system, identifying modulations of the host cell systems in humans during HIV-1 infection may be crucial for the development of immune based therapies. Here, we quantified the changes of the proteome in human CD4+ T cells upon HIV-1 infection, both in vitro and in vivo A SWATH-MS approach was used to measure the proteome of human primary CD4+ T cells infected with HIV-1 in vitro as well as CD4+ T cells from HIV-1-infected patients with paired samples on and off antiretroviral treatment. In the in vitro experiment, the proteome of CD4+ T cells was quantified over a time course following HIV-1 infection. 1,725 host cell proteins and 4 HIV-1 proteins were quantified, with 145 proteins changing significantly during the time course. Changes in the proteome peaked 24 h after infection, concomitantly with significant HIV-1 protein production. In the in vivo branch of the study, CD4+ T cells from viremic patients and those with no detectable viral load after treatment were sorted, and the proteomes were quantified. We consistently detected 895 proteins, 172 of which were considered to be significantly different between the viremic patients and patients undergoing successful treatment. The proteome of the in vitro-infected CD4+ T cells was modulated on multiple functional levels, including TLR-4 signaling and the type 1 interferon signaling pathway. Perturbations in the type 1 interferon signaling pathway were recapitulated in CD4+ T cells from patients. The study shows that proteome maps generated by SWATH-MS indicate a range of functionally significant changes in the proteome of HIV-infected human CD4+ T cells. Exploring these perturbations in more detail may help identify new targets for immune based interventions.

Update of the Swiss guidelines on post-treatment Lyme disease syndrome.

Lyme borreliosis is caused by Borrelia burgdorferi sensu lato infection, which responds well to antibiotic therapy in the overwhelming majority of cases. However, despite adequate antibiotic treatment some patients report persisting symptoms which are commonly summarised as post-treatment Lyme disease syndrome (PTLDS). In 2005, the Swiss Society of Infectious Diseases published a case definition for PTLDS. We aimed to review the scientific literature with a special emphasis on the last 10 years, questioning whether the definitions from 2005 are still valid in the light of current knowledge. Furthermore, we describe the clinical history of infection with Borrelia burgdorferi sensu lato, the estimated prevalence of PTLDS, the possible pathogenesis of PTLDS, and treatment options with an emphasis on clinical studies. In summary, we were unable to find a scientific reason for modification of the PTLDS definitions published in 2005. Thus, the diagnostic criteria remain unchanged, namely documented clinical and laboratory evidence of previous infection with B. burgdorferi, a completed course of appropriate antibiotic therapy, symptoms including fatigue, arthralgia, myalgia, cognitive dysfunction or radicular pain persisting for >6 months, a plausible timely association between documented B. burgdorferi infection and onset of symptoms (i.e., persistent or recurrent symptoms that began within 6 months of completion of a recommended antibiotic therapy for early or late Lyme borreliosis), and exclusion of other somatic or psychiatric causes of symptoms. The main therapeutic options remain cognitive behavioural therapy and low-impact aerobic exercise programmes. Growing and unequivocal evidence confirms that prolonged or repeated antibiotic therapy for PTLDS is not beneficial, but potentially harmful and therefore contraindicated. The Guidelines of the Swiss Society of Infectious Diseases offer an evidence based, diagnostic and therapeutic framework for physicians caring for patients suffering from presumptive PTLDS in Switzerland.

Herd effect from influenza vaccination in non-healthcare settings: a systematic review of randomised controlled trials and observational studies.

Influenza vaccination programmes are assumed to have a herd effect and protect contacts of vaccinated persons from influenza virus infection. We searched MEDLINE, EMBASE, the Cumulative Index to Nursing and Allied Health Literature (CINAHL), Global Health and the Cochrane Central Register of Controlled Trials (CENTRAL) from inception to March 2014 for studies assessing the protective effect of influenza vaccination vs no vaccination on influenza virus infections in contacts. We calculated odds ratios (ORs) and 95% confidence intervals (CIs) using a random-effects model. Of 43,082 screened articles, nine randomised controlled trials (RCTs) and four observational studies were eligible. Among the RCTs, no statistically significant herd effect on the occurrence of influenza in contacts could be found (OR: 0.62; 95% CI: 0.34-1.12). The one RCT conducted in a community setting, however, showed a significant effect (OR: 0.39; 95% CI: 0.26-0.57), as did the observational studies (OR: 0.57; 95% CI: 0.43-0.77). We found only a few studies that quantified the herd effect of vaccination, all studies except one were conducted in children, and the overall evidence was graded as low. The evidence is too limited to conclude in what setting(s) a herd effect may or may not be achieved.