bims-ainimu 2025-11-30 papers

Issue of 2025–11–30
four papers selected by
Pedro Escoll Guerrero, Institut Pasteur

bioRxiv. 2025 Nov 15. pii: 2025.11.15.688116. [Epub ahead of print]

Systems analysis reveals alternate metabolic states adopted by Mycobacterium tuberculosis across species.

Jonathan Padilla-Gomez, Rachel McGinn, Yisha Liang, Kendra Libby, Alison E Ringel, Charles Evavold, Bryan D Bryson.

Mycobacterium tuberculosis (Mtb) persists within macrophages, yet how different host species shape bacterial state remains poorly understood. Here, we directly compared the intracellular transcriptome of Mtb during infection of human and mouse macrophages, revealing distinct host-imposed microenvironments that drive the pathogen into separable metabolic states. Lipid metabolism and regulatory circuits were prominently remodeled, with mouse macrophages inducing iron- and oxidative-stress responses while human macrophages promoted fatty acid import programs. Using fluorescent fatty acid tracing, we uncovered a striking species-specific phenotype: Mtb forms intracellular lipid inclusions (ILIs) in murine macrophages but not in human macrophages. This phenotype was independent of culture media, macrophage ontogeny, or host antimicrobial factors such as nitric oxide and itaconate. Access of Mtb to host-derived lipids required the ESX-1 secretion system and was inversely correlated with host triacylglycerol (TAG) synthesis. Inhibition of TAG formation in human macrophages partially restored Mtb ILI formation, revealing a metabolic gate that governs lipid flow between host lipid droplets and intracellular Mtb. Together, these findings establish a cross-species framework for decoding host-driven bacterial metabolic states and identify a key barrier limiting Mtb's access to host lipid stores in human macrophages.

DOI: https://doi.org/10.1101/2025.11.15.688116

Nat Commun. 2025 Nov 26. 16(1): 10551

Itaconate transport across the plasma membrane and Salmonella-containing vacuole via MCT1/4 modulates macrophage antibacterial activity.

Qingcai Meng, Chengxi Li, Yuping Cai, Ying Chen, Xiaoqing Chen, Xin Wang, Biling Zhang, Yue Zhang, Feng Liu, Meixin Chen.

Itaconate accumulates in macrophages upon bacterial infection, and manifests antibacterial activity. Convincing evidence substantiates that itaconate is transported across the plasma membrane and vacuolar membrane, but the molecular bases underlying bidirectional transport of itaconate across membranes and its effects on intracellular bacterial replication are less known. Here, we identify MCT1 and MCT4 as bidirectional transporters of itaconate. In addition to modulating itaconate concentration as transporters at the plasma membrane, MCT1 and MCT4 function as itaconate transporters at Salmonella-containing vacuole (SCV). Upon Salmonella infection, MCT1 and MCT4 transport itaconate into SCV facilitated by RAB32. Itaconate is also secreted out of cells through MCT1 and MCT4 as the infection persists. The suppression of MCT1 and MCT4-dependent itaconate secretion increases the overall concentration of itaconate and the proportion of itaconate-targeted Salmonella intracellularly, consequently inhibiting Salmonella replication. Our study thus offers valuable insights into itaconate transport during bacterial infection and provides proof of principle for the development of itaconate-dependent therapeutic strategies.

DOI: https://doi.org/10.1038/s41467-025-65582-6

mBio. 2025 Nov 24. e0314725

Amino acid decarboxylation preserves Salmonella fitness during phagocyte-derived oxidative stress.

Alyssa Margolis, Lin Liu, Ju-Sim Kim, Steffen Porwollik, Michael McClelland, Andrés Vázquez-Torres.

Successful establishment of infection by non-typhoidal Salmonella depends upon its ability to resist the antimicrobial defenses of the host innate immune response. To withstand the membrane depolarization that potentiates the killing activity of reactive oxygen species (ROS) produced by the phagocyte NADPH oxidase, Salmonella employs metabolic adaptations that maintain intracellular pH homeostasis and membrane energetics. Here, we identify amino acid decarboxylation as a critical determinant of Salmonella virulence and resistance to the oxidative pressures within the host environment. The proton-consuming decarboxylation of L-arginine preserves intracellular ∆pH and enhances Salmonella survival against the bactericidal effects of ROS, while downstream polyamine biosynthesis aids in bacterial recovery following ROS exposure. Polyamines alone cannot substitute for the immediate, protective impact of proton-consuming decarboxylation during oxidative stress killing. Specifically, we show that Salmonella relies on the combined activity of the inducible arginine AdiA and the ornithine SpeF decarboxylases for resistance to oxidative stress, and that this activity is essential for Salmonella virulence during systemic infection. Together, amino acid decarboxylation and polyamine biosynthesis play complementary, but distinct roles in Salmonella adaptation to phagocyte-derived oxidative stress, providing a new framework for understanding how amino acid catabolism influences bacterial survival in the host.
IMPORTANCE: Salmonellae have been causing disease in humans since at least the Neolithic Revolution, yet non-typhoidal Salmonella infections remain a significant public health challenge. The success of Salmonella as a pathogen stems, in part, from its ability to subvert and survive the host response of macrophages. The amino acid L-arginine is critical for Salmonella enterica serovar Typhimurium virulence and resistance to reactive oxygen species produced by the phagocyte NADPH oxidase. The precise mechanisms by which L-arginine fosters oxidative stress resistance have remained unclear. In this report, we demonstrate that Salmonella relies on the proton-consuming decarboxylation of L-arginine and ornithine to promote resistance against the acute cytotoxicity emanating from the phagocyte NADPH oxidase. On the other hand, polyamines synthesized downstream of L-arginine and ornithine decarboxylation aid in the recovery phase. Our findings redefine the physiological role of amino acid decarboxylation, establishing it as a critical defense mechanism against oxidative stress that is functionally distinct from polyamine biosynthesis. By disentangling the regulatory and functional roles of individual decarboxylases, our study clarifies a long-standing ambiguity in the field and highlights how Salmonella exploits complementary metabolic pathways during its adaptation to oxidative stress in the host.

Keywords: Salmonella; gram-negative bacteria; host-pathogen interactions; intracellular pathogens; macrophages; metabolism; oxidative stress; pathogenesis

DOI: https://doi.org/10.1128/mbio.03147-25

bioRxiv. 2025 Nov 12. pii: 2025.11.12.688034. [Epub ahead of print]

SLC11A2 affects nutritional immunity in the gut epithelium.

Emilia S Norberg, Trina L Westerman, Eddy Cruz, Summer D Bushman, Eric P Skaar, Johanna R Elfenbein, Leigh A Knodler.

There is a constant tug-of-war for transition metals at the pathogen-host interface. A goal of the vertebrate host is to modulate the availability of metals to pathogens, in a process known as nutritional immunity, but pathogens have evolved numerous countermeasures to regulate intracellular trace metal levels. The bioavailability of trace metals therefore shapes the outcome of disease. In the human body, epithelial cells lining the intestine are a major site of metal absorption. Intestinal epithelial cells (IECs) are also a target for invading enteric pathogens but the contribution of epithelium-intrinsic factors towards nutritional immunity has been understudied. Using Salmonella enterica serovar Typhimurium (STm) harboring metal-responsive fluorescent reporters in a bovine ligated intestinal loop infection model, we mapped the spatiotemporal nature of metal competition during enteric salmonellosis. We show that STm experiences a temporal, cell-specific restriction of iron, manganese, and zinc in the intestinal mucosa during the early stages of infection. We have further studied the contribution of the broad specificity metal cation transporter, SLC11A2, in IECs to nutritional immunity against STm. Knockout of SLC11A2 in IECs leads to enhanced replication of STm, indicating a protective role for this transporter. Using fluorescence-based biosensors and bacterial gene deletion mutants, we pinpoint manganese and iron restriction as the mechanism by which SLC11A2 limits bacterial proliferation. We conclude that SLC11A2-mediated sequestration of metals is an intrinsic defense mechanism of the intestinal epithelium against enteric bacteria.
Significance statement: There is limited source of trace metals in the gut that invading pathogens and the infected host must compete for. Using Salmonella enterica as a model enteric pathogen, along with fluorescent reporters that respond to metal ion availability, we traced the sites of metal ion limitation in the intestinal mucosa to intestinal epithelial cells (IECs) and phagocytes in the underlying lamina propria. We further show that SLC11A2 (NRAMP2), which is the sole SLC11 family member expressed in IECs and localizes to the apical membrane and endosomal network, limits the intracellular proliferation of Salmonella enterica by withholding iron and manganese. Therefore SLC11A2-mediated nutritional immunity is an IEC-intrinsic defense mechanism that protects against microbial pathogens.

DOI: https://doi.org/10.1101/2025.11.12.688034