Lactate cross-talk in host-pathogen interactions

Abstract

Lactate is the main product generated at the end of anaerobic glycolysis or during the Warburg effect and its role as an active signalling molecule is increasingly recognised. Lactate can be released and used by host cells, by pathogens and commensal organisms, thus being essential for the homeostasis of host-microbe interactions. Infection can alter this intricate balance, and the presence of lactate transporters in most human cells including immune cells, as well as in a variety of pathogens (including bacteria, fungi and complex parasites) demonstrates the importance of this metabolite in regulating host-pathogen interactions. This review will cover lactate secretion and sensing in humans and microbes, and will discuss the existing evidence supporting a role for lactate in pathogen growth and persistence, together with lactate's ability to impact the orchestration of effective immune responses. The ubiquitous presence of lactate in the context of infection and the ability of both host cells and pathogens to sense and respond to it, makes manipulation of lactate a potential novel therapeutic strategy. Here, we will discuss the preliminary research that has been carried out in the context of cancer, autoimmunity and inflammation.

Keywords: host–pathogen interactions; immunometabolism; infection; lactate.

Figure 1.. Mechanisms of lactate-driven bacterial pathogenesis.

Bacterial pathogens have been demonstrated to use lactate in multiple ways to enhance their pathogenicity. (1) S. aureus generated lactate polarises innate immune cells to an immunotolerant state allowing persistence of biofilms. (2) Lactate can be used as a sole carbon source by a variety of bacteria, or bacteria can use lactate as fuel to enhance growth [32,86]. Enhanced growth is seen in Pseudomonas and other bacteria. (3) Reactive oxygen species are a key bactericidal mechanism used by innate immune cells. Lactate enables bacteria to manipulate oxygen metabolism and thus evade killing, a key mechanism for the persistence of S. aureus [87]. (4) Many bacteria including N. meningitidis and S. aureus colonise the nasopharynx, and the ability to invade is crucial in the move to becoming pathogenic. Lactate utilisation genes have been demonstrated to be required for this step [88]. (5) Bacteria lacking lactate utilisation genes have reduced in vivo pathogenicity in a variety of animal models of infection, this has been shown for Neisseria species and H. influenzae [89]. (6) Complement-mediated killing is reduced in the presence of lactate, mediated by lactate permease [90]. Created using Biorender.com.

Figure 2.. Glycolysis is increased during Mycobacterium tuberculosis infection.

Glycolysis is induced in the lungs of Mycobacterium tuberculosis (M.tb) infected hosts, which results in lactate secretion. This increased in glycolysis upon M.tb infection has been shown in the lungs of guinea pigs, mice, rabbits, non-human primates and humans. Alveolar macrophages are the first M.tb cellular target and, inside them, lactate can be used by M.tb as a carbon source, enhancing pathogen survival and cell growth. Lactate can also be exported through different specific transporters, which results in the acidification of the extracellular milieu. This can promote an altered cytokine response as well as tissue destruction. Created using Biorender.com.

Figure 3.. Lactate cross-talk between Candida albicans and phagocytic immune cells.

The main pattern recognition receptors (PRRs) involved in the recognition of C. albicans are C-type lectin receptors (CLRs) and Toll-like receptors (TLRs) expressed on the surface of innate immune cells with high phagocytic capacity (neutrophils, macrophages and dendritic cells). Sensing of C. albicans triggers a metabolic shift towards glycolysis, which is essential for the effective production and release of proinflammatory cytokines such as TNF, IL1β and IL-6. Active glycolysis results in the production of lactate, which can be exported through different lactate transporters including MCT1, MCT4 and GPR81, depending on cell type (see Table 2). Once this lactate is in the extracellular milieu C. albicans can take it up through the Jen and Gpr1 transporters and use it to thrive in nutrient-restricted body niches. Lactate can not only be used as a carbon source, fuelling metabolic pathways such as the glyoxylate shunt, but it can also alter cell wall composition. These changes largely impact the ability of the host to mount an effective immune response. One of the best-described strategies is the masking of β-glucan, which results in decreased macrophage recognition and neutrophil recruitment. Furthermore, when C. albicans uses lactate as the main carbon source, biofilm formation, as well as resistance to antifungal drugs such as fluconazole, are increased. Created using Biorender.com.

Figure 4.. Lactate directed host and pathogen therapeutic avenues.

Lactate directed therapeutics can be considered to target host or pathogen utilisation of lactate. In the host, vaccination of mice with recombinant lctP was partially protective against N. meningitidis bacteraemia. Supplementing germ-free mice with either d-lactate or LAB improved the phagocytic capacity of Kupffer cells in the liver preventing bacteriaemia. Inhibition of lactate utilisation tools such as MCT, LDH or the lactate receptor GPR81 has been demonstrated to improve viral clearance, reduce tumour burden while deletion of GPR81 increases susceptibility to inflammation. For pathogen directed therapies inhibition of lactate transporters prevents growth of plasmodium falciparum, and in other bacteria deletion of lctP causes reduced virulence in vivo. Lactate transporters are crucial for Candida to avoid antifungal drugs. LctP, lactate permease; LAB, lactic acid-producing bacteria; MCT, monocarboxylate transporters (lactate transporters in vertebrates) and LDH, lactate dehydrogenase. Created using Biorender.com.