Exaggerated IL-17A activity in human in vivo recall responses discriminates active tuberculosis from latent infection and cured disease.

Host immune responses at the site of infection can mediate pathogenesis of tuberculosis (TB) and onward transmission of infection. We hypothesized that pathological immune responses would be enriched at the site of host-pathogen interactions modeled by a standardized tuberculin skin test (TST) challenge in patients with active TB compared to those without disease, and interrogated immune responses by genome-wide transcriptional profiling. We show exaggerated interleukin-17A (IL-17A) and T helper 17 (T17) responses among 48 individuals with active TB compared to 191 with latent TB infection, associated with increased neutrophil recruitment and matrix metalloproteinase-1 expression, both involved in TB pathogenesis.

Transcriptional response modules characterize IL-1β and IL-6 activity in COVID-19.

Dysregulated IL-1β and IL-6 responses have been implicated in the pathogenesis of severe Coronavirus Disease 2019 (COVID-19). Innovative approaches for evaluating the biological activity of these cytokines are urgently needed to complement clinical trials of therapeutic targeting of IL-1β and IL-6 in COVID-19. We show that the expression of IL-1β or IL-6 inducible transcriptional signatures (modules) reflects the bioactivity of these cytokines in immunopathology modelled by juvenile idiopathic arthritis (JIA) and rheumatoid arthritis.

Viral infection triggers interferon-induced expulsion of live Cryptococcus neoformans by macrophages.

Cryptococcus neoformans is an opportunistic human pathogen, which causes serious disease in immunocompromised hosts. Infection with this pathogen is particularly relevant in HIV+ patients, where it leads to around 200,000 deaths per annum. A key feature of cryptococcal pathogenesis is the ability of the fungus to survive and replicate within the phagosome of macrophages, as well as its ability to be expelled from host cells via a novel non-lytic mechanism known as vomocytosis.

Clinical and Economic Impact of Implementing OVIVA Criteria on Patients With Bone and Joint Infections in Outpatient Parenteral Antimicrobial Therapy.

The OVIVA study demonstrated noninferiority for managing bone and joint infections (BJIs) with oral antibiotics. We report that 79.7% of OPAT patients being treated for BJIs at our center would be eligible for oral antibiotics, saving a median (IQR) 19.

Pathogenesis of HIV-1 and Mycobacterium tuberculosis co-infection.

Co-infection with Mycobacterium tuberculosis is the leading cause of death in individuals infected with HIV-1. It has long been known that HIV-1 infection alters the course of M. tuberculosis infection and substantially increases the risk of active tuberculosis (TB).

Tumor Necrosis Factor (TNF) Bioactivity at the Site of an Acute Cell-Mediated Immune Response Is Preserved in Rheumatoid Arthritis Patients Responding to Anti-TNF Therapy.

The impact of anti-tumor necrosis factor (TNF) therapies on inducible TNF-dependent activity in humans has never been evaluated . We aimed to test the hypothesis that patients responding to anti-TNF treatments exhibit attenuated TNF-dependent immune responses at the site of an immune challenge. We developed and validated four context-specific TNF-inducible transcriptional signatures to quantify TNF bioactivity in transcriptomic data.

In Vivo Molecular Dissection of the Effects of HIV-1 in Active Tuberculosis.

Increased risk of tuberculosis (TB) associated with HIV-1 infection is primarily attributed to deficient T helper (Th)1 immune responses, but most people with active TB have robust Th1 responses, indicating that these are not sufficient to protect against disease. Recent findings suggest that favourable outcomes following Mycobacterium tuberculosis infection arise from finely balanced inflammatory and regulatory pathways, achieving pathogen control without immunopathology. We hypothesised that HIV-1 and antiretroviral therapy (ART) exert widespread changes to cell mediated immunity, which may compromise the optimal host protective response to TB and provide novel insights into the correlates of immune protection and pathogenesis.

Paradoxical reactions and immune reconstitution inflammatory syndrome in tuberculosis.

The coalescence of the HIV-1 and tuberculosis (TB) epidemics in Sub-Saharan Africa has had a significant and negative impact on global health. The availability of effective antimicrobial treatment for both HIV-1 (in the form of highly active antiretroviral therapy (HAART)) and TB (with antimycobacterial agents) has the potential to mitigate the associated morbidity and mortality. However, the use of both HAART and antimycobacterial therapy is associated with the development of inflammatory paradoxical syndromes after commencement of therapy.

HIV-1 infection of macrophages dysregulates innate immune responses to Mycobacterium tuberculosis by inhibition of interleukin-10.

Human immunodeficiency virus (HIV)-1 and Mycobacterium tuberculosis (M. tuberculosis) both target macrophages, which are key cells in inflammatory responses and their resolution. Therefore, we tested the hypothesis that HIV-1 may modulate macrophage responses to coinfection with M.

Epistasis and immunity: the role of genetic interactions in autoimmune diseases.

Autoimmune disorders are a complex and varied group of diseases that are caused by breakdown of self-tolerance. The aetiology of autoimmunity is multi-factorial, with both environmental triggers and genetically determined risk factors. In recent years, it has been increasingly recognized that genetic risk factors do not act in isolation, but rather the combination of individual additive effects, gene-gene interactions and gene-environment interactions determine overall risk of autoimmunity.