No terms to describe proinflammatory pathways at the non-cellular level

[genegodbold]

PathGO has terms that describe proinflammatory processes at the cellular level:

1. PATHGO_0000005 (non-specific T cell activation factor)
2. PATHGO_0000010 (mediates non-specific T-cell activation)

but it lacks terms to describe how microbial pathogenesis can involve the molecular manipulation of proinflammatory pathways. It might be thought that microbes would only want to dampen these activities and this is generally true, but sometimes the bug appears to want to rev up host pro-inflammatory processes. SARS-CoV has at least five proteins (of its 29) that appear to specifically provoke host inflammatory pathways over and above the normal innate immune system detection and response pathways. I think (but am not sure) that this is rare for a virus. SARS-CoV-2 appears to also have a few of these proinflammatory proteins.

Here are some bacterial ones, note how many activate inflammasomes (Issue #176). Perhaps we could make a term that covers this? I did this under Issue Something like "Stimulates host inflammasome" (maybe a child under the parent "modulates host inflammasome") and also a "Host inflammasome stimulatory factor" (perhaps a child under the parent "Host inflammasome modulatory factor". I have not yet identified any microbial factors that suppress host inflammasomes.

1. Aeromonas cytotoxic enterotoxin (Act) is secreted via a T2SS [PMID24199174]. Act causes degeneration of crypts and villi of the small intestine in rats. Act activates proinflammatory cytokine and eicosanoid cascades in host macrophages and a rat intestinal epithelial cell line which leads to tissue damage and a fluid secretory response [PMID11895956].
2. After six hours of incubation secreted Hcp1 of E. coli, but not Hcp2, causes significantly higher levels of host HBMEC release of interleukin-1 (IL-1) and IL-8 [PMID22184413].
3. Alpha-hemolysin of S. aureus facilitates the generation of CXC chemokine gradients in a posttranscriptional manner and potentiates CXC chemokine-induced homing of neutrophils into the lung and airway. This creates neutrophil-mediated inflammation, which is necessary for bacterial attachment and invasion [PMID18823272]. Alpha-hemolysin activates pyrin domain containing 3 inflammasome (NLRP3) to induce production of interleukin-1beta and pyroptosis. NLRP-3 induced necrosis causes severe pulmonary injury and pneumonia in its host. Nlrp3-/- mice showed significantly lower mortality than wild-type mice [PMID22279123].
4. Anthrax lethal factor activates the host nucleotide-binding domain leucine-rich repeat pyrin domain-containing 1B (NLRP1B) inflammasome by cleaving NLRP1B after Lys44 (PMID30872531].
5. Borrelia burgdorferi B07 has RGD motifs and associates with alpha3beta1 integrins during a mouse model of infection [PMID17822440]. This association activates matrix metallopreteases and proinflammatory cytokines that is mediated by JNK but not p38 MAPK [PMID16785564].
6. IpaB of Shigellae can cause pyropotosis in macrophages via activation of caspase-1 [PMID11157939].
7. Both TcdA and TcdB of Clostridioides difficile are able to activate the inflammasome to secrete interleukin-1beta with TcdB able to induce inflammasome activation at much lower concentrations than TcdA [PMID20398664]. TcdA induction of the inflammasome in infected cells is dependent on its ability to glucosylate the host Rho protein. This glucosylation is absolutely required for tissue damage and an inflammatory response in vivo [PMID27271747]. Toxin A has a median lethal dose in mice of 4.5 micrograms per kg of bodyweight (90 ng per mouse) [PMID21199912]. It can cause disease in the absence of TcdB [PMID21615333].
8. C. jejuni CDT directly mediates the release of proinflammatory IL-8 from intestinal epithelial cells [PMID19307212].
9. Cytolethal distending toxin of Aggregatibacter actinomycetemcomitans activates host caspase-1 via the NLRP3 inflammasome in macrophages [PMID25644004].
10. Enterohemolysin of E. coli appears to play the role of an enhancer in cytotoxicity and also to stimulate greater release of IL-1b in the THP-1 macrophage-like cell line [PMID23209696].
11. Expression of the sopE gene contributes to colitis in a murine model of Salmonella enterica infection. It can induce intestinal inflammation independent of SipA and SopE2 and in the absence of SopB [PMID14742523]. Intestinal inflammation appears to be due to Rho GTPase activation and downstream effects resulting in caspase-1 induction. This results in the maturation and release of the proinflammatory cytokines IL-1 and IL-18 [PMID19683679].
12. Full length DupA of Helicobacter pylori induced significant production of IL-12p40, IL-12p70, and IL-23 (associated with the Th1 immune response) in human PBMCs. Monocytes were identified as the PBMC subpopulation that were responsible for the secretion of these cytokines [PMID20533870]. DupA appears to induce IL-8 production in human peripheral blood mononuclear cells [PMID20938460].
13. HBL enterotoxin from Bacillus cereus activates the NLRP3 inflammasome with secretion of IL-1beta and IL-18 and instigation of pyroptosis. Inhibition of the inflammasome prevented B. cereus-induced lethality. Inflammasome activation was a requirement for mortality [PMID30531979].
14. In guinea pigs inoculated intrarectally with 1 x 10^9 S. flexneri, those given bacteria expressing OspE showed severe inflammation, internal hemorrhaging, and diarrhea while those not expressing OspE did not manifest these pathological features [PMID19489119].
15. In mice, intranasally administered LasB from P. aeruginosa induced significant weight loss, inflammation, injury and death [PMID28790180]. IL-1 signaling drives neutrophilic inflammation during lung infection with Pseudomonas aeruginosa. Host IL-1beta (UniProtP01584) maturation is facilitated by LasB independent of the host inflammasome [PMID32979835].
16. IpgB2 from Shigella activates host NOD1 upon bacterial invasion of epithelial cells [PMID19043560].
17. Macrophages infected with the mutant M. smegmatis overexpressing PPE11 from M. tuberculosis produced greater quantities of interleukin-1beta, IL-6, and TNF and suffered greater cell death. Similar cytokine changes were observed in the sera of infected mice [PMID30366125].
18. Mutant M. spegmatis bacteria expressing the PPE44 cell wall protein caused more macrophage death and increased expression of inflammatory cytokines IL-6 and IL-12p40 when compared to wild-type bacteria [PMID28743081].
19. ORF8 from SARS-CoV-2 is a protein of 121 residues that is able to interact with host IL-17 as determined by yeast two-hybrid and immunoprecipitation assays. A GST pulldown experiment indicated that ORF8 could also bring down the host IL17 receptor (IL17R). Inhibition of the IL-17 pathway using antibodies to IL17 receptor protected mice from the inflammation induced by ORF8 [PMID33723527]. The ORF8 gene is hypervariable [PMID33468697]-[PMID33361333]. ORF8 is dispensable. SARS-CoV-2 variants in which ORF8 is deleted have been associated with milder symptoms and better disease outcomes [PMID33685621].

Attribution

https://orcid.org/0000-0002-5702-4690

[jproesch]

@genegodbold do the terms added for issues 175 & 176 cover this?

'enhances host inflammasome activation' http://purl.obolibrary.org/obo/pathgo/PATHGO_0000349 'inhibits host inflammasome activation' http://purl.obolibrary.org/obo/pathgo/PATHGO_0000350 'modulates host inflammasome activation' http://purl.obolibrary.org/obo/pathgo/PATHGO_0000348

[genegodbold]

@jproesch It will cover more of them, thank you. I'm sure that there will be "leftovers" for which there is insufficient evidence to assign a term, but we can look over those later. This is a recursive process of knowledge generation. Just getting more sequences tucked away nicely into terms is a good goal.

[jproesch]

@genegodbold excellent. I'll leave this open for now