Evaluation of Berberine as an Adjunct to TB Treatment.

Tuberculosis (TB) is the global health problem with the second highest number of deaths from a communicable disease after COVID-19. Although TB is curable, poor health infrastructure, long and grueling TB treatments have led to the spread of TB pandemic with alarmingly increasing multidrug-resistant (MDR)-TB prevalence. Alternative host modulating therapies can be employed to improve TB drug efficacies or dampen the exaggerated inflammatory responses to improve lung function. Here, we investigated the adjunct therapy of natural immune-modulatory compound berberine in C57BL/6 mouse model of pulmonary TB. Berberine treatment did not affect Mtb growth in axenic cultures; however, it showed increased bacterial killing in primary murine bone marrow-derived macrophages and human monocyte-derived macrophages. Ad libitum berberine administration was beneficial to the host in combination with rifampicin and isoniazid. Berberine adjunctive treatment resulted in decreased lung pathology with no additive or synergistic effects on bacterial burdens in mice. Lung immune cell flow cytometry analysis showed that adjunctive berberine treatment decreased neutrophil, CD11b+ dendritic cell and recruited interstitial macrophage numbers. Late onset of adjunctive berberine treatment resulted in a similar phenotype with consistently reduced numbers of neutrophils both in lungs and the spleen. Together, our results suggest that berberine can be supplemented as an immunomodulatory agent depending on the disease stage and inflammatory status of the host.

In Vivo Antigen Expression Regulates CD4 T Cell Differentiation and Vaccine Efficacy against Mycobacterium tuberculosis Infection.

New vaccines are urgently needed against Mycobacterium tuberculosis (Mtb), which kills more than 1.4 million people each year. CD4 T cell differentiation is a key determinant of protective immunity against Mtb, but it is not fully understood how host-pathogen interactions shape individual antigen-specific T cell populations and their protective capacity. Here, we investigated the immunodominant Mtb antigen, MPT70, which is upregulated in response to gamma interferon (IFN-γ) or nutrient/oxygen deprivation of in vitro-infected macrophages. Using a murine aerosol infection model, we compared the in vivo expression kinetics of MPT70 to a constitutively expressed antigen, ESAT-6, and analyzed their corresponding CD4 T cell phenotype and vaccine protection. For wild-type Mtb, we found that in vivo expression of MPT70 was delayed compared to ESAT-6. This delayed expression was associated with induction of less differentiated MPT70-specific CD4 T cells but, compared to ESAT-6, also reduced protection after vaccination. In contrast, infection with an MPT70-overexpressing Mtb strain promoted highly differentiated KLRG1+CX3CR1+ CD4 T cells with limited lung-homing capacity. Importantly, this differentiated phenotype could be prevented by vaccination, and against the overexpressing strain, vaccination with MPT70 conferred protection similar to vaccination with ESAT-6. Together, our data indicate that high in vivo antigen expression drives T cells toward terminal differentiation and that targeted vaccination with adjuvanted protein can counteract this phenomenon by maintaining T cells in a protective less differentiated state. These observations shed new light on host-pathogen interactions and provide guidance on how future Mtb vaccines can be designed to tip the immune balance in favor of the host.IMPORTANCE Tuberculosis, caused by Mtb, constitutes a global health crisis of massive proportions and the impact of the current coronavirus disease 2019 (COVID-19) pandemic is expected to cause a rise in tuberculosis-related deaths. Improved vaccines are therefore needed more than ever, but a lack of knowledge on protective immunity hampers their development. The present study shows that constitutively expressed antigens with high availability drive highly differentiated CD4 T cells with diminished protective capacity, which could be a survival strategy by Mtb to evade T cell immunity against key antigens. We demonstrate that immunization with such antigens can counteract this phenomenon by maintaining antigen-specific T cells in a state of low differentiation. Future vaccine strategies should therefore explore combinations of multiple highly expressed antigens and we suggest that T cell differentiation could be used as a readily measurable parameter to identify these in both preclinical and clinical studies.

Lessons from Bacillus Calmette-Guérin: Harnessing Trained Immunity for Vaccine Development.

Vaccine design traditionally focuses on inducing adaptive immune responses against a sole target pathogen. Considering that many microbes evade innate immune mechanisms to initiate infection, and in light of the discovery of epigenetically mediated innate immune training, the paradigm of vaccine design has the potential to change. The Bacillus Calmette-Guérin (BCG) vaccine induces some level of protection against Mycobacterium tuberculosis (Mtb) while stimulating trained immunity that correlates with lower mortality and increased protection against unrelated pathogens. This review will explore BCG-induced trained immunity, including the required pathways to establish this phenotype. Additionally, potential methods to improve or expand BCG trained immunity effects through alternative vaccine delivery and formulation methods will be discussed. Finally, advances in new anti-Mtb vaccines, other antimicrobial uses for BCG, and "innate memory-based vaccines" will be examined.

Pathology of TB/COVID-19 Co-Infection: The phantom menace.

Tuberculosis (TB) and coronavirus disease 2019 (COVID-19) are currently the two main causes of death among infectious diseases. There is an increasing number of studies trying to elucidate the interactions between Mycobacterium tuberculosis and SARS-CoV-2. Some of the first case reports point to a worsening of respiratory symptoms in co-infected TB/COVID-19 individuals. However, data from the cohort studies has shown some conflicting results. This study proposes to conduct a systematic review on the current literature on TB/COVID-19 co-infection cohorts, evaluating clinical and epidemiological data, focusing on its implications to the immune system. From an immunological perspective, the TB/COVID-19 co-infection has the potential to converge in a "perfect storm". The disorders induced by each pathogen to the immunomodulation tend to induce an unbalanced inflammatory response, which can promote the progression and worsening of both diseases. Understanding the nature of the interactions between M. tuberculosis and SARS-CoV-2 will be crucial for the development of therapeutic strategies against co-infection.

Case Report: Coronavirus Disease and Pulmonary Tuberculosis in Patients with Human Immunodeficiency Virus: Report of Two Cases.

Coinfection of SARS-CoV-2/Mycobacterium tuberculosis (MTB) in patients with HIV/AIDS has not been previously reported. Here, we present two cases of coinfection of SARS-CoV-2 and MTB in patients with HIV. The first case is a 39-year-old patient who was admitted with a 7-day history of fever, myalgia, headache, and cough. The second patient is a 43-year-old man who had a 1-month history of cough with hemoptoic sputum, evolving to mild respiratory distress in the last 7 days. Both patients already had pulmonary tuberculosis and subsequently developed SARS-CoV-2 infection during the 2020 pandemic. Nonadherence to antiretroviral treatment may have been a factor in the clinical worsening of the patients.

Infections and diabetes: Risks and mitigation with reference to India.

BACKGROUND AND AIMS: The link between diabetes and increased risk of infectious disease has long been recognized, but has re-entered sharp focus following the COVID-19 pandemic. METHODS: A literature search was conducted in PubMed for articles in English on diabetes and infection. RESULTS: Diabetes predisposes to infections through alterations in innate and acquired immune defenses. Outcomes of infection are worse in people with uncontrolled diabetes, and infection can worsen hyperglycemia in hitherto well controlled diabetes (bidirectional relationship). Diabetes does not increase the risk of infection with COVID-19 per se, but predisposes to severe disease and poor outcomes. COVID-19 has also been linked to deterioration of glycemic control as well as new-onset diabetes. CONCLUSIONS: Clinicians caring for people with diabetes should be aware of the increased risk of infections in this population, as well as the possibility of worsening hyperglycemia. A holistic approach with frequent monitoring of blood glucose levels and appropriate titration of medications, along with close attention to nutritional status, is essential to ensure the best possible outcomes.

Case Report: COVID-19 Recovery from Triple Infection with Mycobacterium tuberculosis, HIV, and SARS-CoV-2.

COVID-19, designated as SARS-CoV-2, has caused millions of infections worldwide, including in patients with concomitant infections. Here, we report two unusual cases of patients with triple infections of SARS-CoV-2, Mycobacterium tuberculosis, and HIV. Both cases were confirmed through microbiological and immunological studies. The acute respiratory phase in both patients was treated with supplemental oxygen. Antituberculosis and antiretroviral therapies were started simultaneously. In 2 weeks, both patients demonstrated clinical improvement and recovery from COVID-19. Our findings suggest that even in cases of triple infection, clinical management together with respiratory therapy contributes to patient survival.

Impact of COVID-19 pandemic response on uptake of routine immunizations in Sindh, Pakistan: An analysis of provincial electronic immunization registry data.

BACKGROUND: COVID-19 pandemic has affected routine immunization globally. Impact will likely be higher in low and middle-income countries with limited healthcare resources and fragile health systems. We quantified the impact, spatial heterogeneity, and determinants for childhood immunizations of 48 million population affected in the Sindh province of Pakistan. METHODS: We extracted individual immunization records from real-time provincial Electronic Immunization Registry from September 23, 2019, to July 11, 2020. Comparing baseline (6 months preceding the lockdown) and the COVID-19 lockdown period, we analyzed the impact on daily immunization coverage rate for each antigen by geographical area. We used multivariable logistic regression to explore the predictors associated with immunizations during the lockdown. RESULTS: There was a 52.5% decline in the daily average total number of vaccinations administered during lockdown compared to baseline. The highest decline was seen for Bacille Cal-mette Guérin (BCG) (40.6% (958/2360) immunization at fixed sites. Around 8438 children/day were missing immunization during the lockdown. Enrollments declined furthest in rural districts, urban sub-districts with large slums, and polio-endemic super high-risk sub-districts. Pentavalent-3 (penta-3) immunization rates were higher in infants born in hospitals (RR: 1.09; 95% CI: 1.04-1.15) and those with mothers having higher education (RR: 1.19-1.50; 95% CI: 1.13-1.65). Likelihood of penta-3 immunization was reduced by 5% for each week of delayed enrollment into the immunization program. CONCLUSION: One out of every two children in Sindh province has missed their routine vaccinations during the provincial COVID-19 lockdown. The pool of un-immunized children is expanding during lockdown, leaving them susceptible to vaccine-preventable diseases. There is a need for tailored interventions to promote immunization visits and safe service delivery. Higher maternal education, facility-based births, and early enrollment into the immunization program continue to show a positive association with immunization uptake, even during a challenging lockdown.