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Science (New York, N.Y.) Oct 2023Disruption of cellular activities by pathogen virulence factors can trigger innate immune responses. Interferon-γ (IFN-γ)-inducible antimicrobial factors, such as the...
Disruption of cellular activities by pathogen virulence factors can trigger innate immune responses. Interferon-γ (IFN-γ)-inducible antimicrobial factors, such as the guanylate binding proteins (GBPs), promote cell-intrinsic defense by attacking intracellular pathogens and by inducing programmed cell death. Working in human macrophages, we discovered that GBP1 expression in the absence of IFN-γ killed the cells and induced Golgi fragmentation. IFN-γ exposure improved macrophage survival through the activity of the kinase PIM1. PIM1 phosphorylated GBP1, leading to its sequestration by 14-3-3σ, which thereby prevented GBP1 membrane association. During infection, the virulence protein TgIST interfered with IFN-γ signaling and depleted PIM1, thereby increasing GBP1 activity. Although infected cells can restrain pathogens in a GBP1-dependent manner, this mechanism can protect uninfected bystander cells. Thus, PIM1 can provide a bait for pathogen virulence factors, guarding the integrity of IFN-γ signaling.
Topics: Humans; GTP-Binding Proteins; Immunity, Innate; Interferon-gamma; Proto-Oncogene Proteins c-pim-1; Toxoplasma; Toxoplasmosis; Virulence Factors; Macrophages; 14-3-3 Proteins; Host-Pathogen Interactions
PubMed: 37797010
DOI: 10.1126/science.adg2253 -
Annual Review of Microbiology Sep 2023Apicomplexan parasites constitute more than 6,000 species infecting a wide range of hosts. These include important pathogens such as those causing malaria and... (Review)
Review
Apicomplexan parasites constitute more than 6,000 species infecting a wide range of hosts. These include important pathogens such as those causing malaria and toxoplasmosis. Their evolutionary emergence coincided with the dawn of animals. Mitochondrial genomes of apicomplexan parasites have undergone dramatic reduction in their coding capacity, with genes for only three proteins and ribosomal RNA genes present in scrambled fragments originating from both strands. Different branches of the apicomplexans have undergone rearrangements of these genes, with having massive variations in gene arrangements spread over multiple copies. The vast evolutionary distance between the parasite and the host mitochondria has been exploited for the development of antiparasitic drugs, especially those used to treat malaria, wherein inhibition of the parasite mitochondrial respiratory chain is selectively targeted with little toxicity to the host mitochondria. We describe additional unique characteristics of the parasite mitochondria that are being investigated and provide greater insights into these deep-branching eukaryotic pathogens.
Topics: Animals; Mitochondria; Toxoplasma; Biological Evolution; Malaria
PubMed: 37406344
DOI: 10.1146/annurev-micro-032421-120540 -
Public Health Action Aug 2023A unit supported by Médecins Sans Frontières (MSF) cares for patients with advanced HIV at Donka National Hospital, Conakry, Guinea.
CONTEXT
A unit supported by Médecins Sans Frontières (MSF) cares for patients with advanced HIV at Donka National Hospital, Conakry, Guinea.
OBJECTIVE
To determine the factors associated with the occurrence of death in patients hospitalised in the unit between 2017 and 2021.
DESIGN
This was a retrospective analysis of routine data from patients hospitalised with advanced HIV.
RESULTS
A total of 3,718 patients were included, with a median age of 40 years (IQR 33-51), of whom 2,241 (60.3%) were women. The mean mortality rate was 33.6% ( = 1,240), down from 40% in 2017 to 29% in 2021, but this was not statistically significant. The period most at risk of death was the first 25 days of hospitalisation. Among these patients, TB (43.8%) and toxoplasmosis (11.4%) were the most frequent diagnoses. After multivariate analysis using Cox regression, the factors associated with death were age 25-49 years (adjusted hazard ratio [aHR] 1.60; = 0.002) or ≥50 years (aHR 1.80; < 0.001), the presence of respiratory (aHR 1.23; = 0.001) or abdominal symptoms (aHR 1.26; < 0.001) and readmission (aHR 0.54; < 0.001).
CONCLUSION
Patients aged 25-49 years or older, or those presenting with respiratory or abdominal signs require increased surveillance, as they are at the greatest risk of dying from the disease, especially during the first 25 days of hospitalisation.
PubMed: 37529554
DOI: 10.5588/pha.23.0009