https://www.clinicalmicrobiologyandinfection.com/article/S1198-743X(14)65090-4/pdf

Treating infections caused by carbapenemase-producing Enterobacteriaceae

The use of animal models has been invaluable for studying the pathogenesis of Mycobacterium tuberculosis infection, as well as for testing the efficacy of vaccines and drug regimens for tuberculosis. Among the applied animal models, nonhuman primates, particularly macaques, share the greatest anatomical and physiological similarities with humans. As such, macaque models have been used for investigating tuberculosis pathogenesis and preclinical testing of drugs and vaccines. This review focuses on published major studies which illustrate how the rhesus and cynomolgus macaques have enriched and may continue to advance the field of global tuberculosis research.

Monkey Models of Tuberculosis: Lessons Learned

Among the animal models of tuberculosis (TB), the non-human primates, particularly rhesus macaques (Macaca fascicularis) and cynomolgus macaques (Macaca mulatta), share the greatest anatomical and physiological similarities with humans. Macaques are highly susceptible to Mycobacterium tuberculosis infection and manifest the complete spectrum of clinical and pathological manifestations of TB as seen in humans. Therefore, the macaque models have been used extensively for investigating the pathogenesis of M. tuberculosis infection and for preclinical testing of drugs and vaccines against TB. This review focuses on published major studies that exemplify how the rhesus and cynomolgus macaques have enhanced and may continue to advance global efforts in TB research.

Non-Human Primate Models of Tuberculosis

Tuberculosis (TB) is a granulomatous disease that has affected humanity for thousands of years. The production of cytokines, such as IFN-γ and TNF-α, is fundamental in the formation and maintenance of granulomas and in the control of the disease. Recently, the introduction of TNF-α-blocking monoclonal antibodies, such as Infliximab, has brought improvements in the treatment of patients with chronic inflammatory diseases, but this treatment also increases the risk of reactivation of latent tuberculosis. Our objective was to analyze, in an in vitro model, the influence of Infliximab on the granulomatous reactions and on the production of antigen-specific cytokines (TNF-α, IFN-γ, IL-12p40, IL-10 and IL-17) from beads sensitized with soluble Bacillus Calmette-Guerin (BCG) antigens cultured in the presence of peripheral blood mononuclear cells (PBMC) from TB patients. We evaluated 76 individuals, with tuberculosis active, treated and subjects with positive PPD. Granuloma formation was induced in the presence or absence of Infliximab for up to 10 days. The use of Infliximab in cultures significantly blocked TNF-α production (p <0.05), and led to significant changes in granuloma structure, in vitro, only in the treated TB group. On the other hand, there was a significant reduction in the levels of IFN-γ, IL-12p40, IL-10 and IL-17 after TNF-α blockade in the three experimental groups (p <0.05). Taken together, our results demonstrate that TNF-α blockade by Infliximab directly influenced the structure of granuloma only in the treated TB group, but negatively modulated the production of Th1, Th17 and regulatory T cytokines in the three groups analyzed.

/pdf/tnf-a-blockade-impairs-in-vitro-tuberculous-granuloma-flzkwhq2l4.pdf

TNF-α blockade impairs in vitro tuberculous granuloma formation and down modulate Th1, Th17 and Treg cytokines.

Health-care-associated infections by multi-drug-resistant bacteria constitute one of the greatest challenges to modern medicine. Bacterial pathogens devise various mechanisms to withstand the activity of a wide range of antimicrobial compounds, among which the acquisition of carbapenemases is one of the most concerning. In Klebsiella pneumoniae, the dissemination of the K. pneumoniae carbapenemase is tightly connected to the global spread of certain clonal lineages. Although antibiotic resistance is a key driver for the global distribution of epidemic high-risk clones, there seem to be other adaptive traits that may explain their success. Here, we exploited the power of deep transcriptome profiling (RNA-seq) to shed light on the transcriptomic landscape of 37 clinical K. pneumoniae isolates of diverse phylogenetic origins. We identified a large set of 3346 genes which was expressed in all isolates. While the core-transcriptome profiles varied substantially between groups of different sequence types, they were more homogenous among isolates of the same sequence type. We furthermore linked the detailed information on differentially expressed genes with the clinically relevant phenotypes of biofilm formation and bacterial virulence. This allowed for the identification of a diminished expression of biofilm-specific genes within the low biofilm producing ST258 isolates as a sequence type-specific trait.

/pdf/deep-transcriptome-profiling-of-clinical-klebsiella-2aq574k0jt.pdf

Deep transcriptome profiling of clinical Klebsiella pneumoniae isolates reveals strain and sequence type-specific adaptation.

Establishment of a neonatal rhesus macaque model to study Mycobacterium tuberculosis infection.

Tuberculosis (TB) is the leading cause of death in AIDS patients worldwide; the earliest opportunistic infection occurring in conjunction with HIV; an accelerant of HIV replication and immune system deterioration. Co-infection with Mycobacterium tuberculosis (Mtb) and HIV is an increasing global emergency. Little is known regarding the early events of Mtb infection in humans especially infants. There is an urgent need for a clinically relevant animal model that mimics TB disease in human children to better understand early immune responses, pathogenicity and disease progression in newborn/infants.

/pdf/neonatal-macaque-model-to-study-mycobacterium-tuberculosis-465qazt0hx.pdf

Magdalena Cepeda

Papers

Establishment of a neonatal rhesus macaque model to study Mycobacterium tuberculosis infection.

Neonatal macaque model to study Mycobacterium tuberculosis infection in pediatric AIDS

Engineering of macaque CD4+ T cells and CD34+ hematopoietic stem cells resistant to in vitro SIV infection using zinc finger nucleases