Chronic Infection Research Articles

Genetic variability of hepatitis B virus in acute and in different phases of chronic infection in Brazil

The selection pressure imposed by the host immune system impacts on hepatitis B virus (HBV) variability. This study evaluates HBV genetic diversity, nucleos(t)ide analogs resistance and HBsAg escape mutations in HBV patients under distinct selective pressures. One hundred and thirteen individuals in different phases of HBV infection were included: 13 HBeAg-positive chronic infection, 9 HBeAg-positive chronic hepatitis, 47 HBeAg-negative chronic infection (ENI), 29 HBeAg-negative chronic hepatitis (ENH) and 15 acute infected individuals. Samples were PCR amplified, sequenced and genetically analyzed for the overlapping POL/S genes. Most HBV carriers presented genotype A (84/113; 74.3%), subgenotype A1 (67/84; 79.7%), irrespective of group, followed by genotypes D (20/113; 17.7%), F (8/113; 7.1%) and E (1/113; 0.9%). Clinically relevant mutations in polymerase (tL180M/M204V) and in the Major Hydrophilic Region of HBsAg (sY100C, T118A/M, sM133T, sD144A and sG145R) were observed. Our findings, however, indicated that most polymorphic sites were located in the cytosolic loops (CYL1-2) and transmembrane domain 4 (TMD4) of HBsAg. Lower viral loads and higher HBV genetic diversity were observed in ENI and ENH groups (p < 0.001), suggesting that these groups are subjected to a higher selective pressure. Our results provide information on the molecular characteristics of HBV in a diverse clinical setting, and may guide future studies on the balance of HBV quasispecies at different stages of infection.

Chronic and Latent Viral Infections and Leukocyte Telomere Length across the Lifespan of Female and Male Individuals Living with or without HIV

Background: Chronic/latent viral infections may accelerate immunological aging, particularly among people living with HIV (PLWH). We characterized chronic/latent virus infections across their lifespan and investigated their associations with leukocyte telomere length (LTL). Methods: Participants enrolled in the CARMA cohort study were randomly selected to include n = 15 for each decade of age between 0 and &gt;60 y, for each sex, and each HIV status. Cytomegalovirus (CMV), Epstein–Barr virus (EBV), human herpesvirus 8 (HHV-8), herpes simplex virus 1 (HSV-1), and HSV-2 infection were determined serologically; HIV, hepatitis C (HCV), and hepatitis B (HBV) were self-reported. LTLs were measured using monochrome multiplex qPCR. Associations between the number of viruses, LTL, and sociodemographic factors were assessed using ordinal logistic and linear regression modeling. Results: The study included 187 PLWH (105 female/82 male) and 190 HIV-negative participants (105 female/84 male), ranging in age from 0.7 to 76.1 years. Living with HIV, being older, and being female were associated with harbouring a greater number of chronic/latent non-HIV viruses. Having more infections was in turn bivariately associated with a shorter LTL. In multivariable analyses, older age, living with HIV, and the female sex remained independently associated with having more infections, while having 3–4 viruses (vs. 0–2) was associated with a shorter LTL. Conclusions: Our results suggest that persistent viral infections are more prevalent in PLWH and females, and that these may contribute to immunological aging. Whether this is associated with comorbidities later in life remains an important question.

Retinal microglia express more MHC class I and promote greater T-cell-driven inflammation than brain microglia

IntroductionMacrophage function is determined by microenvironment and origin. Brain and retinal microglia are both derived from yolk sac progenitors, yet their microenvironments differ. Utilizing single-cell RNA sequencing (scRNA-seq) data from mice, we tested the hypothesis that retinal and brain microglia exhibit distinct transcriptional profiles due to their unique microenvironments.MethodsEyes and brains from 2-4 month wildtype mice were combined (20 eyes; 3 brains) to yield one biologically diverse sample per organ. Each tissue was digested into single cell suspensions, enriched for immune cells, and sorted for scRNA-seq. Analysis was performed in Seurat v3 including clustering, integration, and differential expression. Multi-parameter flow cytometry was used for validation of scRNA-seq results. Lymphocytic choriomeningitis virus (LCMV) Clone 13, which produces a systemic, chronic, and neurotropic infection, was used to validate scRNA-seq and flow cytometry results in vivo.ResultsCluster analysis of integrated gene expression data from eye and brain identified 6 Tmem119+P2ry12+ microglial clusters. Differential expression analysis revealed that eye microglia were enriched for more pro-inflammatory processes including antigen processing via MHC class I (14.0-fold, H2-D1 and H2-K1) and positive regulation of T-cell immunity (8.4-fold) compared to brain microglia. Multi-parameter flow cytometry confirmed that retinal microglia expressed 3.2-fold greater H2-Db and 263.3-fold more H2-Kb than brain microglia. On Day 13 and 29 after LCMV infection, CD8+ T-cell density was greater in the retina than the brain.DiscussionOur data demonstrate that the microenvironment of retina and brain differs, resulting in microglia-specific gene expression changes. Specifically, retinal microglia express greater MHC class I by scRNA-seq and multi-parameter flow cytometry, resulting in a possibly enhanced capability to stimulate CD8+ T-cell inflammation during LCMV infection. These results may explain tissue-specific differences between retina and brain during systemic viral infections and CD8+ T-cell driven autoimmune disease.

Occult hepatitis B infection in children born to HBeAg-positive women confers a low long-term risk for HBsAg-positive infection.

Mother-to-child transmission (MTCT) has been the main cause of chronic hepatitis B virus (HBV) infection, particularly in East Asia. Hepatitis B immunoglobulin (HBIG) and vaccination given directly after birth effectively prevents hepatitis B surface antigen (HBsAg)-positive (overt) HBV infection, but occult hepatitis B infection (OBI) may develop despite adequate prophylaxis. The aim of this study was to investigate the long-term outcome in children born to mothers with very high HBV DNA levels with special focus on children discovered in early childhood with OBI. One-year and long-term outcome regarding overt and occult HBV infection were analysed in 66 children born to hepatitis B e antigen (HBeAg)-positive mothers, and were compared with one-year outcome in 69 children born to HBeAg-negative mothers. The children were born between 1998 and 2018. Six children born to HBeAg-positive mothers developed overt chronic HBV infection, in two cases after normal pregnancies and despite HBIG and vaccination, but never when nucleotide analogue treatment was given during pregnancy. OBI with HBV DNA detected in serum in the absence of surface antigen (HBsAg) was observed in four children at the age of 1year. One of them was transiently HBsAg-positive at the age of 7years. At long-term follow-up, six children had overt chronic infection, one had OBI and six had previous OBI or positive anti-HBc suggesting resolved unidentified infections. The results indicate that children born to mothers with high HBV DNA levels have approximately 10% risk to develop OBI despite antiviral treatment, vaccination and HBIG, but that such OBI confers a minimal long-term risk for overt infection, at least in immunocompetent children.

Alternative treatment of recurrent Clostridioides difficile infection in adults by fecal transplantation: an overview of phase I–IV studies from Clinicaltrials.gov

BackgroundFecal microbiota transplantation (FMT) is an interventional approach to treat chronic and recurrent Clostridioides difficile infection (CDI). However, there is insufficient evidence regarding its effectiveness and safety. Clinical trials have been conducted to inspect the safety and effectiveness of FMT with and without comparison to pharmacological treatments.AimThis review explored the treatment of CDI in adults using FMT and evaluated the safety of this intervention based on phase I–IV studies registered on Clinicaltrials.gov.MethodA comprehensive search of Clinicaltrials.gov was conducted to identify relevant studies that investigated CDI in adults. Data on study type, study design, sample size, intervention details, and outcomes related to FMT were examined and evaluated.ResultsIn total, 13 clinical trials on FMT for CDI published through 17 November 2023 were identified, all of which were interventional studies. The investigation focused on both terminated and completed studies. Basic and advanced outcome measures were examined.ConclusionSome studies were terminated during phase II, and FMT was less effective than antibiotics such as vancomycin and fidaxomicin. However, colonoscopy and oral FMT were explored in several completed studies with promising results, but the evidence remains limited and inconclusive.

Accelerated infected wound healing by probiotic-based living microneedles with long-acting antibacterial effect

Delays in infected wound healing are usually a result of bacterial infection and local inflammation, which imposes a significant and often underappreciated burden on patients and society. Current therapies for chronic wound infection generally suffer from limited drug permeability and frequent drug administration, owing to the existence of a wound biofilm that acts as a barrier restricting the entry of various antibacterial drugs. Here, we report the design of a biocompatible probiotic-based microneedle (MN) patch that can rapidly deliver beneficial bacteria to wound tissues with improved delivery efficiency. The probiotic is capable of continuously producing antimicrobial substances by metabolizing introduced glycerol, thereby facilitating infected wound healing through long-acting antibacterial and anti-inflammatory effects. Additionally, the beneficial bacteria can remain highly viable (>80 %) inside MNs for as long as 60 days at 4 °C. In a mouse model of Staphylococcus aureus-infected wounds, a single administration of the MN patch exhibited superior antimicrobial efficiency and wound healing performance in comparison with the control groups, indicating great potential for accelerating infected wound closure. Further development of live probiotic-based MN patches may enable patients to better manage chronically infected wounds.

Pigs in southern Italy are exposed to three ruminant pathogens: an analysis of seroprevalence and risk factors analysis study

BackgroundPigs are susceptible to several ruminant pathogens, including Coxiella burnetti, Schmallenberg virus (SBV) and bovine viral diarrhea virus (BVDV). These pathogens have already been described in the pig population, although the dynamics of the infection and the impact on pig farms are currently unclear. The aim of this work was to evaluate the presence of these infections in the pig population of the Campania region, southern Italy, and to evaluate the risk factors associated with a greater risk of exposure.ResultsA total of 414 serum samples belonging to 32 herds were tested for the presence of antibodies against SBV, Coxiella, and BVD using commercial multispecies ELISA kits. SBV (5.3%) was the most prevalent pathogen, followed by Coxiella (4.1%) and BVD (3%). The risk factors included in the study (age, sex, province, farming system, ruminant density and major ruminant species) had no influence on the probability of being exposed to BVD and Coxiella, except for the location, in fact more pigs seropositive to Coxiella were found in the province of Caserta. However, the univariate analysis highlighted the influence of age, location, and sex on exposure to SBV. The subsequent multivariate analysis statistically confirmed the importance of these factors. The presence of neutralizing antibodies for SBV and BVDV, or antibodies directed towards a specific phase of infection for Coxiella was further confirmed with virus-neutralization assays and phase-specific ELISAs in a large proportion of positive samples. The presence of high neutralizing antibody titers (especially for SBV) could indicate recent exposures. Twelve of the 17 positive samples tested positive for antibodies against Coxiella phase I or II antigens, indicating the presence of both acute and chronic infections (one animal tested positive for both phases antibodies).ConclusionsOur study indicates a non-negligible exposure of pigs from southern Italy to the above pathogens. Further studies are necessary to fully understand the dynamics of these infections in pigs, the impact on productivity, and the public health consequences in the case of Coxiella.

Observing astrocyte polarization in brains from mouse chronically infected with Toxoplasma gondii

Toxoplasma gondii (T. gondii) is a protozoan parasite that infects approximately one-third of the global human population, often leading to chronic infection. While acute T. gondii infection can cause neural damage in the central nervous system and result in toxoplasmic encephalitis, the consequences of T. gondii chronic infection (TCI) are generally asymptomatic. However, emerging evidence suggests that TCI may be linked to behavioral changes or mental disorders in hosts. Astrocyte polarization, particularly the A1 subtype associated with neuronal apoptosis, has been identified in various neurodegenerative diseases. Nevertheless, the role of astrocyte polarization in TCI still needs to be better understood. This study aimed to establish a mouse model of chronic TCI and examine the transcription and expression levels of glial fibrillary acidic protein (GFAP), C3, C1q, IL-1α, and TNF-α in the brain tissues of the mice. Quantitative real-time PCR (qRT-PCR), enzyme-linked immunosorbent assay, and Western blotting were employed to assess these levels. Additionally, the expression level of the A1 astrocyte-specific marker C3 was evaluated using indirect fluorescent assay (IFA). In mice with TCI, the transcriptional and expression levels of the inflammatory factors C1q, IL-1α, and TNF-α followed an up-down-up pattern, although they remained elevated compared to the control group. These findings suggest a potential association between astrocyte polarization towards the A1 subtype and synchronized changes in these three inflammatory mediators. Furthermore, immunofluorescence assay (IFA) revealed a significant increase in the A1 astrocytes (GFAP+C3+) proportion in TCI mice. This study provides evidence that TCI can induce astrocyte polarization, a biological process that may be influenced by changes in the levels of three inflammatory factors: C1q, IL-1α, and TNF-α. Additionally, the release of neurotoxic substances by A1 astrocytes may be associated with the development of TCI.

Galectin-3-ITGB1 Signaling Mediates Interleukin 10 Production of Hepatic Conventional Natural Killer Cells in Hepatitis B Virus Transgenic Mice and Correlates with Hepatocellular Carcinoma Progression in Patients

Background and Aims: The outcomes of HBV infections are related to complex immune imbalances; however, the precise mechanisms by which HBV induces immune dysfunction are not well understood. Methods: HBV transgenic (HBs-Tg) mice were used to investigate intrahepatic NK cells in two distinct subsets: conventional NK (cNK) and liver-resident NK (LrNK) cells during a chronic HBV infection. Results: The cNK cells, but not the LrNK cells, were primarily responsible for the increase in the number of bulk NK cells in the livers of ageing HBs-Tg mice. The hepatic cNK cells showed a stronger ability to produce IL-10, coupled with a higher expression of CD69, TIGIT and PD-L1, and lower NKG2D expression in ageing HBs-Tg mice. A lower mitochondrial mass and membrane potential, and less polarized localization were observed in the hepatic cNK cells compared with the splenic cNK cells in the HBs-Tg mice. The enhanced galectin-3 (Gal-3) secreted from HBsAg+ hepatocytes accounted for the IL-10 production of hepatic cNK cells via ITGB1 signaling. For humans, LGALS3 and ITGB1 expression is positively correlated with IL-10 expression, and negatively correlated with the poor clinical progression of HCC. Conclusions: Gal-3-ITGB1 signaling shapes hepatic cNK cells but not LrNK cells during a chronic HBV infection, which may correlate with HCC progression.

Assessing microplastics-antibiotics coexistence induced ciprofloxacin-resistant Pseudomonas aeruginosa at a water region scale

Microplastics (MPs) waste is widespread globally in water systems. The opportunistic human pathogen Pseudomonas aeruginosa can cause serious acute and chronic infections that are notoriously difficult to treat. Ciprofloxacin (CIP) is broadly applied as an anti-P. aeruginosa drug. A growing evidence reveals that antibiotic-resistance genes-carrying Pseudomonas aeruginosa were detected on MPs forming plastisphere due to their adsorbability along with high occurrence of CIP in water environments. The MPs-niched CIP-resistant P. aeruginosa has been likely to emerge as an unignorable public health issue. Here, we offered a novel approach to assess the development of CIP-resistant P. aeruginosa under MPs-antibiotic coexistence at a water region scale. By combing the adsorption isotherm models used to estimate CIP condensation around MPs and a pharmacokinetic/pharmacodynamic-based microbial population dynamic model, we predicted the P. aeruginosa development on CIP-adsorbed MPs in waters. Our assessment revealed a high antibiotic resistance in the P. aeruginosa populations (∼50 %) with a wider range of waterborne total cell counts (∼10−2–104 cfu mL−1) among water regions in that the resistance proportion was primarily determined by CIP pollution level and relative abundance of various polymer type of MPs. We implicate that water region-specific MPs were highly likely to provide media for P. aeruginosa propagation. Our results highlight the importance of antibiotic-resistant pathogen colonization−emerging environmental medium interactions when addressing global threat from MPs pollution, in the context of MPs-antibiotics co-contamination assessment and for the continued provision of water system management.

PSPC1 Binds to HCV IRES and Prevents Ribosomal Protein S5 Binding, Inhibiting Viral RNA Translation

Hepatitis C virus (HCV) infects the human liver, and its chronic infection is one of the major causes of Hepatocellular carcinoma. Translation of HCV RNA is mediated by an Internal Ribosome Entry Site (IRES) element located in the 5’UTR of viral RNA. Several RNA Binding proteins of the host interact with the HCV IRES and modulate its function. Here, we demonstrate that PSPC1 (Paraspeckle Component 1), an essential paraspeckle component, upon HCV infection is relocalized and interacts with HCV IRES to prevent viral RNA translation. Competition UV-crosslinking experiments showed that PSPC1 interacts explicitly with the SLIV region of the HCV IRES, which is known to play a vital role in ribosomal loading to the HCV IRES via interaction with Ribosomal protein S5 (RPS5). Partial silencing of PSPC1 increased viral RNA translation and, consequently, HCV replication, suggesting a negative regulation by PSPC1. Interestingly, the silencing of PSPC1 protein leads to an increased interaction of RPS5 at the SLIV region, leading to an overall increase in the viral RNA in polysomes. Overall, our results showed how the host counters viral infection by relocalizing nuclear protein to the cytoplasm as a survival strategy.

Characterization of virus‒host recombinant variants of the hepatitis E virus.

Hepatitis E virus (HEV) is a major cause of viral hepatitis. HEV can lead to chronic infection in immunocompromised patients. Ribavirin treatment is currently used to treat such chronic infections. Recently, seven virus-host recombinant viruses were characterized in immunocompromised patients. These viruses have incorporated a portion of a human gene fragment into their genome. We studied the consequences of these insertions on the replication capacity. We found that these inserted fragments could enhance virus replication for five of the seven recombinant variants. We also showed that the recombinant variants with replicative advantages were less sensitive to ribavirin in vitro. Finally, we found that the mechanisms leading to such a replicative advantage do not seem to rely on the post-translational modifications introduced by the human gene fragment that could have modified the function of the viral protein. The mechanisms involved in improving the replication of such recombinant viruses remain to be explored.

Baicalein inhibits biofilm formation of avian pathogenic Escherichia coli in vitro mainly by affecting adhesion

Avian pathogenic Escherichia coli (APEC) is a widespread bacterium that causes significant economic losses to the poultry industry. APEC biofilm formation may result in chronic, persistent, and recurrent infections in clinics, making treatment challenging. Baicalein is a natural product that exhibits antimicrobial and antibiofilm activities. This study investigates the inhibitory effect of baicalein on APEC biofilm formation at different stages. The minimum inhibitory concentration (MIC) of baicalein on APEC was determined, and the growth curve of APEC biofilm formation was determined. The effects of baicalein on APEC biofilm adhesion, accumulation, and maturation were observed using optical microscopy, confocal laser scanning microscopy, and scanning electron microscopy. The biofilm inhibition rate of baicalein was calculated at different stages. The MIC of baicalein against APEC was 256 μg/mL. The process of APEC biofilm maturation takes approximately 48 h after incubation, with initial adhesion completed at 12 h, and cell accumulation finished at 24 h. Baicalein had a significant inhibitory effect on APEC biofilm formation at concentrations above 1 μg/mL (p < 0.01). Notably, baicalein had the highest rate of biofilm formation inhibition when added at the adhesion stage. Therefore, it can be concluded that baicalein is a potent inhibitor of APEC biofilm formation in vitro and acts, primarily by inhibiting cell adhesion. These findings suggests that baicalein has a potential application for inhibiting APEC biofilm formation and provides a novel approach for the prevention and control APEC-related diseases.

Minimally Invasive Semiconductor Laser Surgery Combined with 5-ALA Photodynamic Therapy for a Chronic Hyperplastic Candidiasis Patient Who Is Ineffective to Antifungal Therapy.

Background: Chronic hyperplastic candidiasis (CHC) is a chronic oral mucosal infection caused by Candida, which has potential for malignant transformation. Diagnosing CHC can be challenging due to its various manifestations. In addition, fungal treatments often prove to be ineffective, highlighting the urgent need for a new safe and efficient treatment approach. Given the potential of CHC to transform into malignancy, it is crucial to emphasize dynamic monitoring and follow-up after treatment. Objective: We attempted to investigate the effect of semiconductor laser pretreatment combined with 5-amino-levulinic acid (5-ALA) photodynamic therapy (PDT) for CHC. Methods: We presented the successful treatment of CHC with mild dysplasia in a 30-year-old man using semiconductor laser and 5-ALA PDT after antifungal therapy proved ineffective. Toluidine blue staining, autofluorescence imaging, and DNA image cytometry were combined to dynamically monitor the progress of the disease. Results: We have obtained positive outcomes with the use of laser combined with PDT treatment. The patients experienced only mild adverse reactions after the treatment, and there was no indication of recurrence or malignant transformation during the subsequent follow-up period, as observed through various auxiliary examinations. Conclusions: This case report suggests that semiconductor laser surgery combined with PDT could be a promising treatment option for patients with CHC who do not respond to antifungal therapy. In addition, the use of combined noninvasive examinations might provide a more accurate assessment of malignant transformation in patients with CHC.

Chronic Severe Laryngeal Inflammation Caused by Basidiobolomycosis

Basidiobolomycosis is an uncommon fungal infection primarily found in plants. In humans, it typically affects the skin and gastrointestinal tract on manifestation of the infection. A 29-year-old female presented to our clinic with complaints of shortness of breath and voice changes. On examination, she exhibited severe laryngeal edema. She was initially diagnosed with type 3 hereditary angioedema with a normal C1 inhibitor and later as a case of laryngeal sarcoidosis, treatment for both conditions proved ineffective. Ultimately, after further microbiological assessment, she was diagnosed with chronic granulomatous laryngeal fungal infection caused by the Basidiobolus species. Subsequently, she displayed significant improvement with itraconazole treatment. Chronic laryngeal edema can have various underlying causes. This case underscores the importance of considering fungal pathogens, especially rare ones when assessing such conditions. In cases where the diagnosis is uncertain or standard treatments are ineffective, patient reassessment and repeated laryngeal biopsies are essential.

Dry powder inhalation containing muco-inert ciprofloxacin and colistin co-loaded liposomes for pulmonary P. Aeruginosa biofilm eradication

Pseudomonas aeruginosa (PA), a predominant pathogen in lung infections, poses significant challenges due to its biofilm formation, which is the primary cause of chronic and recalcitrant pulmonary infections. Bacteria within these biofilms exhibit heightened resistance to antibiotics compared to their planktonic counterparts, and their secreted toxins exacerbate lung infections. Diverging from traditional antibacterial therapy for biofilm eradication, this study introduces a novel dry powder inhalation containing muco-inert ciprofloxacin and colistin co-encapsulated liposomes (Cipro-Col-Lips) prepared using ultrasonic spray freeze drying (USFD) technique. This USFD dry powder is designed to efficiently deliver muco-inert Cipro-Col-Lips to the lungs. Once deposited, the liposomes rapidly diffuse into the airway mucus, reaching the biofilm sites. The muco-inert Cipro-Col-Lips neutralize the biofilm-secreted toxins and simultaneously trigger the release of their therapeutic payload, exerting a synergistic antibiofilm effect. Our results demonstrated that the optimal USFD liposomal dry powder formulation exhibited satisfactory in vitro aerosol performance in terms of fine particle fraction (FPF) of 44.44 ± 0.78 %, mass median aerodynamic diameter (MMAD) of 4.27 ± 0.21 μm, and emitted dose (ED) of 99.31 ± 3.31 %. The muco-inert Cipro-Col-Lips effectively penetrate the airway mucus and accumulate at the biofilm site, neutralizing toxins and safeguarding lung cells. The triggered release of ciprofloxacin and colistin works synergistically to reduce the biofilm’s antibiotic resistance, impede the development of antibiotic resistance, and eliminate 99.99 % of biofilm-embedded bacteria, including persister bacteria. Using a PA-beads induced biofilm-associated lung infection mouse model, the in vivo efficacy of this liposomal dry powder aerosol was tested, and the results demonstrated that this liposomal dry powder aerosol achieved a 99.7 % reduction in bacterial colonization, and significantly mitigated inflammation and pulmonary fibrosis. The USFD dry powder inhalation containing muco-inert Cipro-Col-Lips emerges as a promising therapeutic strategy for treating PA biofilm-associated lung infections.

Hepatitis B virus particles in serum contain minus strand DNA and degraded pregenomic RNA of variable and inverse lengths.

This study utilized digital PCR to quantify HBV RNA and HBV DNA within three regions of the HBV genome. Analysis of 75 serum samples from patients with chronic infection showed that HBV RNA levels were higher in core than in S and X regions (median 7.20 vs. 6.80 and 6.58 log copies/mL; p < .0001), whereas HBV DNA levels showed an inverse gradient (7.71 vs. 7.73 and 7.77 log copies/mL, p < .001). On average 80% of the nucleic acid was DNA by quantification in core. The core DNA/RNA ratio was associated with viral load and genotype. In individual patients, the relations between RNA levels in core, S and X were stable over time (n = 29; p = .006). The results suggest that pregenomic RNA is completely reverse transcribed to minus DNA in ≈75% of the virus particles, whereas the remaining 25% contain both RNA and DNA of lengths that reflect variable progress of the polymerase.

Mycobacterium tuberculosis resides in lysosome-poor monocyte-derived lung cells during chronic infection.

Mycobacterium tuberculosis (Mtb) infects lung myeloid cells, but the specific Mtb-permissive cells and host mechanisms supporting Mtb persistence during chronic infection are incompletely characterized. We report that after the development of T cell responses, CD11clo monocyte-derived cells harbor more live Mtb than alveolar macrophages (AM), neutrophils, and CD11chi monocyte-derived cells. Transcriptomic and functional studies revealed that the lysosome pathway is underexpressed in this highly permissive subset, characterized by less lysosome content, acidification, and proteolytic activity than AM, along with less nuclear TFEB, a regulator of lysosome biogenesis. Mtb infection does not drive lysosome deficiency in CD11clo monocyte-derived cells but promotes recruitment of monocytes that develop into permissive lung cells, mediated by the Mtb ESX-1 secretion system. The c-Abl tyrosine kinase inhibitor nilotinib activates TFEB and enhances lysosome functions of macrophages in vitro and in vivo, improving control of Mtb infection. Our results suggest that Mtb exploits lysosome-poor lung cells for persistence and targeting lysosome biogenesis is a potential host-directed therapy for tuberculosis.

The immunoglobulin superfamily ligand B7H6 subjects T cell responses to NK cell surveillance.

Understanding the mechanisms that regulate T cell immunity is critical for the development of effective therapies for diseases associated with T cell dysfunction, including autoimmune diseases, chronic infections, and cancer. Co-inhibitory "checkpoint molecules," such as programmed cell death protein-1, balance excessive or prolonged immune activation by T cell-intrinsic signaling. Here, by screening for mediators of natural killer (NK) cell recognition on T cells, we identified the immunoglobulin superfamily ligand B7H6 to be highly expressed by activated T cells, including patient-infused CD19-targeting chimeric antigen receptor (CAR) T cells. Unlike other checkpoint molecules, B7H6 mediated NKp30-dependent recognition and subsequent cytolysis of activated T cells by NK cells. B7H6+ T cells were prevalent in the tissue and blood of several diseases, and their abundance in tumor tissue positively correlated with clinical response in a cohort of patients with immune checkpoint inhibitor-treated esophageal cancer. In humanized mouse models, NK cell surveillance via B7H6 limited the persistence and antitumor activity of CAR T cells, and its genetic deletion enhanced T cell proliferation and persistence. Together, we provide evidence of B7H6 protein expression by activated T cells and suggest the B7H6-NKp30 axis as a therapeutically actionable NK cell-dependent immune checkpoint that regulates human T cell function.

Hepatitis B Virus Infection: A Mini Review

Hepatitis B and C viruses (HBV and HCV) are the leading causes of end-stage liver disease worldwide. Although there is a potent vaccine against HBV, many new infections are recorded annually, especially in poorly resourced places which have lax vaccination policies. Again, as HBV has no cure and chronic infection is lifelong, vaccines cannot help those already infected. Studies to thoroughly understand the HBV biology and pathogenesis are limited, leaving much yet to be understood about the genomic features and their role in establishing and maintaining infection. The current knowledge of the impact on disease progression and response to treatment, especially in hyperendemic regions, is inadequate. This calls for in-depth studies on viral biology, mainly for the purposes of coming up with better management strategies for infected people and more effective preventative measures for others. This information could also point us in the direction of a cure. Here, we discuss the progress made in understanding the genomic basis of viral activities leading to the complex interplay of the virus and the host, which determines the outcome of HBV infection as well as the impact of coinfections.