Pathogen-pathogen interactions during co-infections

Abstract

For over a century, bacterial infections have been studied through the lens of the one-microbe, one-disease paradigm. However, it is now clear that multi-pathogen infections are common, and many infectious diseases are inherently polymicrobial. These complex infections can involve a variety of pathogens, including viruses, bacteria, fungi, and parasites, with polyviral and viral-bacterial interactions being the most extensively studied. In this review, we focus on polybacterial infections, providing an in-depth analysis of the diverse strategies bacteria employ to thrive in co-infection scenarios. We examine the mechanisms of bacterial competition, competition avoidance through spatial or temporal separation, and cooperation. Given the association of polymicrobial infections with more severe clinical outcomes and heightened antibiotic tolerance, we also explore novel therapeutic targets to treat these increasingly common and complex infections. Although our review summarizes current knowledge, the vast scope of this phenomenon suggests that many more mechanisms remain undiscovered and warrant further investigation.

Keywords: bacterial competition; bacterial pathogens; competition avoidance; pathogen cooperation; polymicrobial infection; polymicrobial infection therapy.

Figure 1

Strategies for survival and growth in polymicrobial environments. The figure illustrates the main strategies employed by bacteria in mixed communities: (1) bacterial competition, where organisms directly antagonize competitors through mechanisms such as production of bacteriocins, delivery of effectors by secretion systems, or metabolic competition for limited resources; (2) competition avoidance, where bacteria minimize direct competition through spatial or temporal separation; and (3) bacterial cooperation, where bacteria engage in mutually beneficial interactions including metabolite sharing, collaborative biofilm formation, and cross-feeding relationships. These strategies are not mutually exclusive, and bacteria often employ multiple approaches simultaneously depending on the environmental conditions and community composition.

Figure 2

Effectors used by bacteria to target other pathogens or host cells in polymicrobial infections. Bacteria enhance their colonization and replication by manipulating host cells and competing against other microbes through the activity of various effectors. These effectors are delivered via contact-independent secretion, including the release of quorum sensing (QS) molecules, secondary metabolites, exopolysaccharides, and unsaturated fatty acids that influence neighboring bacteria, as well as secreted toxins and QS molecules that act toward eukaryotic cells. In contrast, contact-dependent secretion relies on direct contact and the use of secretion systems such as the T4SS, T5SS, T6SS, and T7SS to target other bacteria and T3SS, T6SS, and T7SS to deliver effectors into eukaryotic cells. These strategies contribute to bacterial competition, cooperation, and virulence in different environments.

Figure 3

Therapeutic strategies targeting polymicrobial infections. The illustration depicts a polymicrobial biofilm and various therapeutic approaches that can be used alone or in combination with conventional antibiotics to combat these complex bacterial communities. Antibiofilm molecules may target the extracellular matrix, including matrix-degrading enzymes and dispersal agents that compromise biofilm structural integrity. They may also interfere with biofilm maturation processes. Bacterial cells within the biofilm can be targeted by antimicrobial peptides, which disrupt bacterial cell membranes, and bacteriocins, which provide diverse antimicrobial activity. Quorum-sensing inhibitors interfere with bacterial cell-cell communication through multiple mechanisms, including degradation of signaling molecules and receptor antagonism. This multi-modal approach addresses the various aspects of the polymicrobial pathogen community, potentially offering more effective treatment strategies for polymicrobial infections compared to conventional antibiotics alone.