The evolution of respiratory diseases caused by viruses and bacteria is significantly driven by mutations and antiviral or antibiotic selection pressure and represents a continuous public health challenge. Successful dissemination of these pathogens is achieved through the modulation of the host immune system. In recent years, new insights into intracellular protein-protein interactions (PPIs) have shown that pathogen-directed immune signaling disruption and immune evasion may be common infection mechanisms. Through the analysis of pathogen-derived molecules that modulate the immune system, new therapeutic, diagnostic, or vaccine targets can be identified.

Several PPIs have been identified for infectious bacteria in humans. In pulmonary tuberculosis, for example, a PPI has been identified between early-secreted antigenic target (ESAT-6)-derived molecules from Mycobacterium tuberculosis (M. tuberculosis) and ATF-2 and c-Jun transcription factors. ESAT-6 is an IFN-g inhibitor that reduces the expression of ATF-2 and c-Jun. Lipid M. tuberculosis antigens, such as mannose-capped lipoarabinomannan also induce p38 activation and activate apoptosis in neutrophils, suggesting an interaction between M. tuberculosis-derived antigens and immune system molecules. Other potential PPIs occur through PDZ domains, as the Rv3333c (Ppr1) and Rv3439c (Ppr2) proteases from M. tuberculosis contain a PDZ-interacting domain. PPIs are also known in respiratory virus infections. Molecular mimicry is a common strategy used by viruses to manipulate host cellular mechanisms. For example, unstructured sequences of three to ten consecutive amino acids, known as short linear motifs (SLiMs), are widely used by viruses to target host proteins to modulate host tropism or immune response, conferring them with a high adaptation capacity. Examples are the PDZ-binding motifs (PDZbms) found in some strains of influenza A viruses. The PDZbm sequence, which mimics the natural ligand of PDZ domains, is used by some viral families to target host PDZ proteins and could partially explain their selectivity and sensitivity during the process of infection.

The aim of this Special Issue is to gather research focused on molecules that interact with and modify the immune response, and that could be potential targets for diagnosis, new treatments, or drug design, to help advance our understanding of how pathogen proteins interact with the immune system, and how pharmacological treatment modifies both pathogens and the immune response. We welcome both original research and review articles.

Potential topics include but are not limited to the following:

• Respiratory pathogens such as Mycobacterium tuberculosis and influenza virus
• New mechanisms of pathogen-derived molecules that regulate the host immune response
• Pathogen interactions with host proteins
• Immune evasion driven by pathogen- and host-protein interactions
• Molecular targets involved in the development of drug resistance
• Drug interaction with proteins of the immune response
• Modification by drugs of the immune response against pathogens