Immunometabolism and Pulmonary Infections: Implications for Protective Immune Responses and Host-Directed Therapies

The biology and clinical efficacy of immune cells from patients with infectious diseases or cancer are associated with metabolic programming. Host immune- and stromal-cell genetic and epigenetic signatures in response to the invading pathogen shape disease pathophysiology and disease outcomes. Directly linked to the immunometabolic axis is the role of the host microbiome, which is also discussed here in the context of productive immune responses to lung infections. We also present host-directed therapies (HDT) as a clinically viable strategy to refocus dysregulated immunometabolism in patients with infectious diseases, which requires validation in early phase clinical trials as adjuncts to conventional antimicrobial therapy. These efforts are expected to be continuously supported by newly generated basic and translational research data to gain a better understanding of disease pathology while devising new molecularly defined platforms and therapeutic options to improve the treatment of patients with pulmonary infections, particularly in relation to multidrug-resistant pathogens

KRAS RENAISSANCE(S) in Tumor Infiltrating B Cells in Pancreatic Cancer

KRAS is a driver mutation for malignant transformation. It is found in 30% of all cancers and in 90% of pancreatic cancers. The identification of small molecules selectively inhibiting KRAS mutants has been challenging, yet mutant KRAS has recently been shown to be targeted by tumor-infiltrating lymphocyte (TIL)-derived T cells that confer tumor regression upon adoptive transfer. Furthermore, a human IgG1 monoclonal antibody interfering with mutant KRAS function inside the cell has been described to inhibit growth of KRAS-mutant xenografts in tumor-bearing mice. B cells have been described to infiltrate pancreatic cancer and may be associated with tertiary lymphoid structures associated with good prognosis, or, in contrast, promote tumor growth. However, their function, nor their antigen-specificity has been clearly defined. We discuss here the presence of tumor-infiltrating B cells (TIB) in patients with pancreatic cancer that produce KRAS-mutant specific IgG, underlining that intratumoral T and B cells may exclusively target mutant KRAS. KRAS-specific IgG may, therefore, serve as a readout of the activation of both arms of the anti-tumor adaptive immune armament although some B-cell populations may promote tumor progression

Perspectives on tuberculosis in pregnancy

Tuberculosis (TB) has been recognized as an important cause of morbidity and mortality in pregnancy for nearly a century, but research and efforts to roll out comprehensive TB screening and treatment in high-risk populations such as those with a high prevalence of HIV or other diseases of poverty, have lagged behind similar efforts to address HIV infection in pregnancy and the prevention of mother-to-child-transmission. Immunological changes during pregnancy make the activation of latent TB infection or de novo infection more likely than among non-pregnant women. TB treatment in pregnancy poses several problems that have been under-researched, such as contraindications to anti-TB and anti-HIV drugs and potential risks to the neonate, which are particularly important with respect to second-line TB treatment. Whilst congenital TB is thought to be rare, data from high HIV burden settings suggest this is not the case. There is a need for more studies screening for TB in neonates and observing outcomes, and testing preventative or curative actions. National tuberculosis control programmes (NTPs) should work with antenatal and national HIV programmes in high-burden populations to provide screening at antenatal clinics, or to establish functioning systems whereby pregnant women at high risk can drop in to routine NTP screening stations. (c) 2014 The Authors. Published by Elsevier Ltd on behalf of International Society for Infectious Diseases

Frequency of Mycobacterium tuberculosis-specific CD8+T-cells in the course of anti-tuberculosis treatment

Anti-tuberculosis drug treatment is known to affect the number, phenotype, and effector functionality of antigen-specific T-cells. In order to objectively gauge Mycobacterium tuberculosis (MTB)-specific CD8+ T-cells at the single-cell level, we developed soluble major histocompatibility complex (MHC) class I multimers/peptide multimers, which allow analysis of antigen-specific T-cells without ex vivo manipulation or functional tests. We constructed 38 MHC class I multimers covering some of the most frequent MHC class I alleles (HLA-A*02:01, A*24:02, A*30:01, A*30:02, A*68:01, B*58:01, and C*07:01) pertinent to a South African or Zambian population, and presenting the following MTB-derived peptides: the early expressed secreted antigens TB10.4 (Rv0288), Ag85B (Rv1886c), and ESAT-6 (Rv3875), as well as intracellular enzymes, i.e., glycosyltransferase 1 (Rv2957), glycosyltransferase 2 (Rv2958c), and cyclopropane fatty acid synthase (Rv0447c). Anti-TB treatment appeared to impact on the frequency of multimer-positive CD8+ T-cells, with a general decrease after 6 months of therapy. Also, a reduction in the total central memory CD8+ T-cell frequencies, as well as the antigen-specific compartment in CD45RA - CCR7+ T-cells was observed. We discuss our findings on the basis of differential dynamics of MTB-specific T-cell frequencies, impact of MTB antigen load on T-cell phenotype, and antigen-specific T-cell responses in tuberculosis. (c) 2015 The Authors. Published by Elsevier Ltd on behalf of International Society for Infectious Diseases

Blue Skies research is essential for ending the Tuberculosis pandemic and advancing a personalized medicine approach for holistic management of Respiratory Tract infections

Objectives: Investments into ‘blue skies’ fundamental TB research in low- and middle-income countries (LMICs) have not been forthcoming. We highlight why blue skies research will be essential for achieving global TB control and eradicating TB. // Methods: We review the historical background to early TB discovery research and give examples of where investments into basic science and fundamental ‘blue skies research’ are delivering novel data and approaches to advance diagnosis, management and holistic care for patients with active and latent TB infection. // Findings: The COVID-19 pandemic has shown that making available adequate funding for priority investments into ‘Blue skies research’ to delineate scientific understanding of a new infectious diseases threat to global health security can lead to rapid development and rollout of new diagnostic platforms, treatments, and vaccines. Several advances in new TB diagnostics, new treatments and vaccine development are underpinned by basic science research. // Conclusions: Basic science research focused can pave the way for a personalized medicine approach for management of TB and other Respiratory Tract Infections and preventing long-term functional disability. Transfer of skills and resources by wealthier nations is required to empower researchers in LMICs countries to engage in and lead basic science ‘blue skies research

Human Leukocyte Antigen Class 1 Phenotype Distribution and Analysis in Persons from Central Uganda with Active Tuberculosis and Latent Mycobacterium tuberculosis Infection

Background: The Ugandan population is heavily affected by infectious diseases and Human leukocyte antigen (HLA) diversity plays a crucial role in the host-pathogen interaction and affects the rates of disease acquisition and outcome. The identification of HLA class 1 alleles and determining which alleles are associated with tuberculosis (TB) outcomes would help in screening individuals in TB endemic areas for susceptibility to TB and to predict resistance or progression to TB which would inevitably lead to better clinical management of TB. Aims: To be able to determine the HLA class 1 phenotype distribution in a Ugandan TB cohort and to establish the relationship between these phenotypes and active and latent TB. Methods: Blood samples were drawn from 32 HIV negative individuals with active TB and 45 HIV negative individuals with latent MTB infection. DNA was extracted from the blood samples and the DNA samples HLA typed by the polymerase chain reaction-sequence specific primer method. The allelic frequencies were determined by direct count. Results: HLA-A*02, A*01, A*74, A*30, B*15, B*58, C*07, C*03 and C*04 were the dominant phenotypes in this Ugandan cohort. There were differences in the distribution of HLA types between the individuals with active TB and the individuals with LTBI with only HLA-A*03 allele showing a statistically significant difference (p=0.0136). However, after FDR computation the corresponding q-value is above the expected proportion of false discoveries (q-value 0.2176). Key findings: We identified a number of HLA class I alleles in a population from Central Uganda which will enable us to carry out a functional characterization of CD8+ T-cell mediated immune responses to MTB. Our results also suggest that there may be a positive association between the HLA-A*03 allele and TB implying that individuals with the HLA-A*03 allele are at a higher risk of developing active TB