TABLE 1.
Summary of mammalian factors associated with the host response to UPEC-mediated UTI
| Category or factor | Known or proposed role during UTI | Reference(s) |
|---|---|---|
| Adherence prevention | ||
| Apoptosis/exfoliation | Removal of bound and intracellular UPEC | 10, 60, 81, 166, 176, 177, 189 |
| GAGs | Decreases uroepithelium affinity for and/or inhibits UPEC adherence factors | 120, 158, 196, 197, 199, 237 |
| THP | Binds FimH, innate-adaptive signaling | 172, 190, 192, 193, 195, 225 |
| Antimicrobial peptides | ||
| α-Defensin | Disrupt UPEC membranes | 234, 294 |
| β-Defensin | Disrupt UPEC membranes, DC maturation | 28, 174, 277 |
| Cathelicidin | Disrupt UPEC membranes | 46 |
| Extracellular matrix | ||
| Involucrin | Maintenance of uroepithelium | 215 |
| Suprabasin | Maintenance of uroepithelium | 215 |
| Signaling and cellular function | ||
| Adaptor proteins | ||
| ARH, Dab2, Numb | Alternative clathrin adaptors for UPEC internalization | 64 |
| AP-2 | Primary clathrin adaptor for UPEC internalization | 64 |
| MyD88 | Proinflammatory gene expression | 73 |
| TRIF | Proinflammatory gene expression | 73 |
| TRAM | Proinflammatory gene expression | 73 |
| Enzymes | ||
| AC3 | Proinflammatory gene expression, UPEC internalization suppression | 243, 245 |
| Histone deacetylase 6 | UPEC internalization | 53 |
| Rho GTPases (Rac-1, Cdc42) | Mobilize actin for UPEC internalization | 56, 161, 243 |
| Lysozyme | Cleaves bacterial peptidoglycan | 215 |
| NOS enzymes | Production of bactericidal reactive oxygen radicals, modifies dynamin facilitating UPEC entry into host cells | 130, 132, 181, 205, 281 |
| Kinases | ||
| Aurora A kinase | UPEC internalization | 53 |
| FAK | UPEC internalization | 65 |
| PI3-K | UPEC internalization | 162 |
| PKA | Proinflammatory gene expression, UPEC internalization suppression | 243, 245 |
| Src family kinases | UPEC internalization | 65, 162 |
| Tyrosine kinases | UPEC internalization | 162 |
| Membrane and cytoskeleton | ||
| Actin | UPEC internalization | 162 |
| α-actinin | UPEC internalization | 162 |
| Bid | Apoptosis | 141 |
| Cholesterol | UPEC internalization | 64 |
| Clathrin | UPEC internalization | 64 |
| Caveolin-1 | UPEC internalization | 56, 64, 133 |
| Dynamin | UPEC internalization | 64, 281 |
| Kinesin light chain-2 (kinesin-1 motor complex) | UPEC internalization | 53 |
| Microtubules | UPEC internalization | 53 |
| Vinculin | UPEC internalization | 162 |
| Receptors | ||
| β1 and α3 integrin | UPEC internalization | 65 |
| CD46 | Opsonized UPEC internalization | 157 |
| CD48 | UPEC internalization | 18, 139 |
| CD55 | Regulator of the complement system, UPEC internalization | 133, 215 |
| Crry | Opsonized UPEC internalization | 247 |
| GM-1 ganglioside | UPEC internalization | 133 |
| ICAM-1 and β2 integrin | Required for efficient neutrophil migration to the infected urinary tract | 3, 227 |
| TLR4 | Recognition of UPEC by LPS and/or fimbriae in the bladder and kidney | 12, 14, 72, 79, 104-106, 175, 228, 229 |
| TLR5 | Recognition of UPEC flagellin in the bladder | 7 |
| TLR11 | Recognition of UPEC in the kidney | 296 |
| Uroplakin IIIa | Apoptosis/exfoliation | 258, 259 |
| Signaling molecules | ||
| Calcium | Apoptosis/exfoliation, proinflammatory gene expression, UPEC internalization | 64, 245, 259 |
| cAMP | Intracellular UPEC vesicle dynamics, mobilize actin for UPEC internalization, proinflammatory gene expression | 29, 243, 245 |
| Transcription factors | ||
| CREB | Proinflammatory gene activation | 245 |
| NF-κB | Apoptosis, proinflammatory gene activation | 73, 142, 245 |
| Iron homeostasis | ||
| Lactoferrin | Iron sequestration, disruption of Gram- negative bacterial membranes | 2, 49, 61, 90, 279 |
| Lcn2 | Bind and sequester enterobactin and enterobactin-like siderophores | 70, 74, 88, 110, 215 |
| Transferrin | Bind and transport iron, disruption of Gram- negative bacterial membranes | 61, 213, 279 |
| Cytokines, chemokines, and complement | ||
| CCL2, CCL4, CCL5, CXCL1 | Migration of T cells, monocytes, macrophages, NK cells, DCs, neutrophils | 121, 122 |
| G-CSF | Neutrophil development and differentiation | 121, 122 |
| IL-6 | Acute phase response, B and T cell activation | 103, 104, 121, 122 |
| IL-8 | Neutrophil migration | 3, 4, 99, 102, 169, 229, 287 |
| IL-17 | Induce cytokine production important for phagocytic cell migration | Sivick et al., submitted |
| IL-1β, IL-12p40, TNF-α | Fever; T cell, NK, macrophage, and endothelial activation; Th1 response, local inflammation | 121, 122 |
| C3, factor B | Complement factors upregulated in response to infection, C3 utilized for UPEC internalization | 215, 247 |
| Phagocytic cells | ||
| Dendritic cells | Bacterial phagocytosis and killing, antigen presentation, IgA secretion | 62, 109, 144, 227, 255 |
| Macrophages | Bacterial phagocytosis and killing, antigen presentation | 63, 109, 121 |
| Neutrophils | Bacterial phagocytosis and killing | 4, 100, 236 |
| Innate-like lymphocytes | ||
| B-1 cells | Secrete IgM | 23, 115 |
| NKT cells | Rapidly secrete cytokines, mediate UPEC clearance | 168, 182 |
| γδ T cells | Rapidly secrete cytokine, including IL-17 | 17, 40, 45, 115, 130, 163; Sivick, et al., submitted |
| Adaptive cellsa | ||
| B cells | Secrete antibody | 109 |
| Th1 cells | Provide B cell help for an appropriate humoral response | 87, 130 |
| Th2 cells | Unknown | NA |
| Th17 cells | May be dispensable for natural adaptive immune protective responses | Sivick, et al., submitted |
| Treg cells | Unknown | NA |
| Antibodya | ||
| IgA | Neutralization, opsonization, complement activation | 58, 116, 122, 217, 249, 263, 264 |
| IgG | Neutralization, opsonization, complement activation | 58, 116, 122, 217, 249, 263, 264 |
| IgM | Mainly complement activation | 58, 116, 122, 217, 249, 263, 264 |
a
In addition to the references cited, Table 2 provides data on humoral and cellular responses to vaccine candidates.