Anti-inflammatory regulatory T cells have lately attracted attention as part of the immune response to
infection, where they counterbalance the protective but pro-inflammatory immune response ...mediated by Th17 cells and especially by the better-known Th1 cells. In chronic infectious diseases there is a delicate balance between pro- and anti-inflammatory responses. While Th1 and Th17 are needed in order to control infection by
, the inflammatory onset can ultimately become detrimental for the host. In this review, we assess current information on the controversy over whether counterbalancing regulatory T cells are promoting pathogen growth or protecting the host.
The progression of tuberculosis from a latent, subclinical infection to active disease that culminates in the transmission of infectious bacilli is determined locally at the level of the granuloma. ...This progression takes place even in the face of a robust immune response that, although it contains infection, is unable to eliminate the bacterium. The factors or environmental conditions that influence this progression remain to be determined. Recent advances have indicated that pathogen-induced dysregulation of host lipid synthesis and sequestration serves a critical role in this transition. The foamy macrophage seems to be a key participant in both sustaining persistent bacteria and contributing to the tissue pathology that leads to cavitation and the release of infectious bacilli.
The evolution between Mycobacterium tuberculosis infection and active tuberculosis is multifactorial and involves different biological scales. The synthesis of ESAT-6 or the induction of alveolar ...macrophage necrosis are key, but to understand it, it is necessary to consider the dynamics of endogenous and exogenous reinfection, drainage of lung parenchyma and respiratory mechanics, local fibrosis processes and blood supply. Paradoxically, the immune response generated by the infection is highly protective (90%) against active tuberculosis, although as it is essentially based on the proliferation of Th1 lymphocytes, it cannot prevent reinfection. Severe immunosuppression can only explain 10% of active tuberculosis cases, while the remainder are attributable to comorbidities, a proinflammatory environment and an unknown genetic propensity. The pathogenic capacity of environmental mycobacteria is discrete, linked to deficits in the innate and acquired immune response. The ability to generate biofilms and the ability of M. ulcerans to generate the exotoxin mycolactone is remarkable.
A major problem with tuberculosis (TB) control is the long duration of drug therapy-both for latent and for active TB. Therapeutic vaccination has been postulated to improve this situation, and to ...this end there are several candidates already in clinical phases of development. These candidates follow two main designs, namely bacilli-directed therapy based on inactivated -whole or -fragmented bacillus (
and RUTI) or fusion proteins that integrate non-replicating bacilli -related antigens (H56 vaccine), and host-directed therapy to reduce the tissue destruction. The administration of inactivated
prevents the "Koch phenomenon" response, and oral administration of heat-killed
prevents excessive neutrophilic infiltration of the lesions. This review also tries to explain the success of
by reviewing its evolution from infection to disease, and highlights the lack of a definitive understanding of the natural history of TB pathology and the need to improve our knowledge on TB immunology and pathogenesis.
Mitofusin 2 (Mfn2) plays a major role in mitochondrial fusion and in the maintenance of mitochondria-endoplasmic reticulum contact sites. Given that macrophages play a major role in inflammation, we ...studied the contribution of Mfn2 to the activity of these cells. Pro-inflammatory stimuli such as lipopolysaccharide (LPS) induced Mfn2 expression. The use of the Mfn2 and Mfn1 myeloid-conditional knockout (KO) mouse models reveals that Mfn2 but not Mfn1 is required for the adaptation of mitochondrial respiration to stress conditions and for the production of reactive oxygen species (ROS) upon pro-inflammatory activation. Mfn2 deficiency specifically impairs the production of pro-inflammatory cytokines and nitric oxide. In addition, the lack of Mfn2 but not Mfn1 is associated with dysfunctional autophagy, apoptosis, phagocytosis, and antigen processing. Mfn2floxed;CreLysM mice fail to be protected from Listeria, Mycobacterium tuberculosis, or LPS endotoxemia. These results reveal an unexpected contribution of Mfn2 to ROS production and inflammation in macrophages.
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•In macrophages, LPS-induced ROS production requires mitochondrial mitofusin 2•Mfn2 is required for the production of cytokines, phagocytosis, and antigen processing•Survival from bacterial infection or septic shock is compromised in Mfn2−/− mice
Tur et al. show that LPS-induced stress in macrophages requires mitofusin 2, which affects mitochondrial respiration and ROS production. The lack of Mfn2 in macrophages blocks the triggering of pro-inflammatory responses, phagocytosis, and antigen presentation.
This is a call to encourage the search for a new vaccine to stop the progression of
infection to tuberculosis (TB) disease. TB is a highly discreet and stigmatized disease, with a massive impact on ...human health. It has killed 1.2 billion people in the last 200 years and still kills 1.5 million people per year. Over the last 20 years, the TB vaccine field has experienced spectacular developments, and we have learned about (1) the importance of the Th1 response in controlling infection, mainly against RD1 and Ag85 antigens; (2) the stability of the antigenic repertoire; (3) the dynamics of
granulomas; or (4) the link between typical and atypical pulmonary TB and the immune status of the host. However, we still do not (1) know how to avoid
infection and reinfection; (2) understand the major role of the increase in lesion size in progression from infection to disease; (3) the role of interlobular septa in encapsulating pulmonary lesions; or (4) the role of neutrophilic infiltration and an exaggerated inflammatory response in the development of TB disease. These are strong reasons to pursue new, imaginative proposals involving both the antibody response and a balanced, tolerant immune response that averts progression toward TB. So far, the scientific mindset has been quite monolithic and has mainly focused on the stimulation of conventional T cells. But this approach has failed. For that reason, we are seeking unconventional perspectives to find a "pink swan," a more efficacious and safer vaccine candidate.
Abstract
Accurate characterization of respiratory bacterial co-infection is critical for guiding empirical antibiotic treatment for hospitalised patients with coronavirus disease 2019 (COVID-19). We ...retrospectively assessed the clinical and analytical predictors of respiratory bacterial co-infection and described the empirical use of antibiotics in COVID-19 hospitalised patients. Respiratory bacterial co-infection was documented in 6.9% (80/1157) of the patients. The predominant bacteria isolates were
Haemophilus influenzae
, followed by
Streptococcus pneumoniae
and
Pseudomonas aeruginosa
. Respiratory bacterial co-infection was associated with having had a positive culture for a respiratory pathogen in the last year (OR = 25.89), dyslipidaemia (OR = 2.52), heart failure (OR = 7.68), ferritin levels < 402 ng/mL (OR = 2.28), leukocyte count > 8.7 × 10
9
/L (OR = 2.4), and patients with chronic obstructive pulmonary disease treated with inhaled corticosteroids (OR = 12.94). Empirical antibiotic treatment was administered in 42.33% of patients, although it declined across the distinct study periods (
p
< 0.001). Patients admitted to intensive care units harbouring co-infection exhibited worse outcomes and more bacterial secondary infections. In conclusion, respiratory bacterial co-infection prevalence was low, although it could lead to unfavourable outcomes. Moreover, the percentage of empirical antibiotic treatment remained high. The study's findings allowed the identification of several predictors for respiratory bacterial co-infection and could help implement adequate antibiotic stewardship measures.
Current data estimate the origin of Mycobacterium tuberculosis complex (MtbC) infection around 73,000 years before the common era (BCE), and its evolution to "modern" lineages around 46,000 BCE. ...Being MtbC a major killer of humanity, the question is how both species could persist. To answer this question, we have developed two new epidemiological models (SEIR type), adapted to sex dimorphism and comparing coinfection and superinfection for different MtbC lineages. We have attributed a higher resistance/tolerance to females to explain the lower incidence noted in this sex, a better health status in the Paleolithic compared to the Neolithic, and a higher dissemination of "modern" lineages compared to "ancient" ones. Our findings show the extraordinary impact caused by "modern" lineages, provoking the extinction of the groups infected. This could only be overcomed by an unprecedented population increase (x20 times in 100 years) and helped with the protection generated by previous infection with "ancient" lineages. Our findings also suggest a key role of female resistance against MtbC. This data obliges us to rethink the growth population parameters in the Paleolithic, which is crucial to understanding the survival of both MtbC and humans, and to decipher the nature of human female resistance against TB.
Over the last decades, research regarding innate immune responses has gained increasing importance. A growing body of evidence supports the notion that the innate arm of the immune system could show ...memory traits. Such traits are thought to be conserved throughout evolution and provide a survival advantage. Several models are available to study these mechanisms. Among them, we find the fruit fly,
Drosophila melanogaster
. This non-mammalian model has been widely used for innate immune research since it naturally lacks an adaptive response. Here, we aim to review the latest advances in the study of the memory mechanisms of the innate immune response using this animal model.
Highlights • 1 Vaccines are screened in multiple animal models and each have merits. • 2 Models which better reflect the human pathology spectrum should be included along with novel “exvivo” models. ...• 3 Integration of experimental data using mathematical models is important.
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