Figure 1.
Acid is found in pathogenesis and defense in diverse symbiotic relationships.
Cellular schematic shows the use of acid in innate and adaptive immunity of plant and animal cells (top). Subversion strategies of five model pathogens discussed in detail are shown in lower insets. Acid is denoted by red or H+. PAMP, pathogen-associated molecular patterns; PRR, pattern recognition receptors; R, (plant) resistance genes; MHC, major histocompatibility complex; SA, salicylic acid; JA, jasmonic acid; OA, oxalic acid.
Figure 2.
Acid's role in initiating adaptive immunity.
An antigen-presenting cell activated by innate PRR will present peptide antigen generated in acidic vesicles to a helper T cell via MHC class II. Activated by this presentation of specific antigen, the helper T cell can then mediate many different immune effector functions, depending on the subtype of helper CD4+ T cell, context, and signals from the APC. Five such major immune effector pathways are suggested here.
Figure 3.
Phylogeny of acidic phagolysosome use in immunity.
Simplified phylogeny of life, marking major hypothesized steps supported by current comparative biology in the co-opting of the acidic phagolysosome system in innate and adaptive immunity (blue). Sister taxon names are illustrative and not necessarily of same phylogenetic rank, and genetic distances are not to scale. All life has innate immunity, but only vertebrates have adaptive immunity (red). Origins of key proteins that regulate the system are shown in green.
Figure 4.
Acid-active cathepsins cleave phagolysosomal antigens in the MHC class II pathway.
Phagocytosed antigens are degraded to peptides (grey) by acids and acid-active cathepsin proteases as the endosomal pH decreases due to fusion with lysosomes (1). During their trafficking from the ER to the cell surface, MHC class II molecules (light green) pass through these acidified vesicles (2). Invariant chain (red) chaperones MHC class II from the ER to an acidified endosome, all the while protecting the peptide binding groove of MHC class II from premature loading (3). Invariant chain is cleaved by cathepsins but leaves the CLIP portion (red triangle) in the MHC peptide binding site (4). In a specialized late endosome, the MHC homolog HLA-DM finally binds to the MHC class II/CLIP complex and releases CLIP (5), allowing other peptides to bind before the MHC class II travels to the cell surface (6). There it can present antigen to T cells (7).
Figure 5.
Coxiella and Brucella use distinct mechanisms for intracellular pathogenesis.
A. C. burnetti thrives in the acidic phagolysosome system, requiring low pH for the transition from quiescent small cell variants (SCV) to metabolically active large cell variants (LCV). Several of the transmembrane proteins that mark the Coxiella-containing vacuole (CCV) through this transition are shown. The Dot/Icm type IV secretion system is used by C. burnetti to deliver proteins into the host cytosol [138], and renovate the lysosome into a CCV [139]. Cb, Coxiella burnetti; Atg, autophagosome; Lys, lysosome. B. Working model of Brucella intracellular parasitism. Brucella-containing vacuoles avoid fusion with acidic lysosomes, and instead traffic to a compartment that is decorated with ER markers for replication. The Type IV secretion system (T4SS) of the pathogen is critical for appropriate trafficking, and mutants that harbor mutations in the T4SS traffic to the lysosome where they are killed. Several T4SS secretion substrates have been identified, and it has been postulated that these molecules contribute to supporting the intracellular lifestyle of the pathogen. Replicative Brucella can exit cells by trafficking along a pathway that involves selective interactions with components of the host cell autophagy biogenesis machinery. Approximate vesicular/vacuolar pH is indicated by color, and the Golgi is generally more acidic than the ER [57, 140–142].
Figure 6.
Stages of Sclerotinia pathogenesis.
Early steps of infection create a reducing environment that dampens host defense responses and inhibits reactive oxygen species (ROS). This allows the fungal pathogen to establish and damage host tissues with cell wall degradative enzymes (CWDE). When eventual apoptotic cascades are induced, recognition occurs but too late for the host plant to prevail. (adapted from [143]).
Table 1.
Notable pathogens evolved for acid management or evasion.