Q. I have a question about H. pylori. I understand that it’s mainly the host’s inflammatory response to the H. pylori‘s presence at the epithelial cell surface that causes the ulcers. Is that mainly due to the cytokines released in response to the bacteria injecting cagA, or do the H. pylori just naturally attract host inflammatory cells by themselves too? I guess my main curiosity is which type of H. pylori cause the most ulcers (the non-cag ones or the cag ones), and can an H. pylori have one or the other cagA or cagV, or do they always have them both when they have them?
A. Yes: it is mainly the host’s inflammatory response to Helicobacter pylori that causes gastritis and ulcers. And you’re right that strains with cagA have a particularly florid inflammatory response. About 50-70% of H. pylori strains are cagA positive; these strains induce a greater inflammatory response in the patient than cagA negative strains. Patients with cagA positive strains have a significantly greater risk for developing ulcers and carcinomas than patients with cagA negative strains.
However, as you alluded to, cagA is not the only thing responsible for the damaging inflammatory response. Here are some other mechanisms by which H. pylori induces inflammation:
1. Toll-like receptor mechanisms.
You might remember from immunology that there are a bunch of ways of activating the innate immune response. One way is through the activation of Toll-like receptors (TLRs), which are specialized cell-surface receptors that recognize certain highly-conserved bacterial features (like flagella, or peptidoglycan). Once TLRs encounter these features, they activate the innate immune system. This is a nice way to activate the immune system in general, because it’s so non-specific! TLRs recognize not just one particular kind of bacterial antigen, but all kinds of antigens, present on many many kinds of bacteria (and somehow they can tell which bacteria are commensals and which are pathogens). The adaptive immune system gets all specific and highly-targeted, but that arm of immunity takes a while to get going.
TLRs are present on gastric epithelial cells. They are able to recognize certain parts of H. pylori and induce an innate immune response, just as described above. It turns out, though, that this pathway plays a pretty minor role in the induction of the innate immune system; other pathways have a greater effect.
2. Non-TLR mechanisms
One really potent stimulator of inflammation is something called Heat Shock Protein 60, a protein present in H. pylori. This protein stimulates the production of IL-6 by macrophages, which leads to inflammation.
3. Other virulence factors
As mentioned, cagA is a potent inducer of inflammation. The cagA gene complex encodes proteins that form a type IV secretion system (a little hypodermic needle-like thing), through which the cagA protein, peptidoglycan, and a bunch of other stuff is injected into the host cell. In addition to cagA, there are a lot of other virulence factors in H. pylori (too many to discuss) that provoke and maintain the inflammatory response. Different strains have different combinations of these virulence factors – which probably accounts for why some strains are so intensely pro-inflammatory and others are less so.
So: cagA positive strains of H. pylori induce a particularly strong inflammatory response (and are particularly likely to cause ulcers). However, cagA negative strains of H. pylorialso induce inflammation (and cause ulcers), using other mechanisms and other virulence factors.
You also asked whether an individual strain of H. pylori can have cagA but not vac A or vice versa. Yes! CagA and vacA don’t always go hand in hand. Some H. pylori strains have neither cagA or vacA; some have one or the other; and some have both. Same goes for the other virulence factors.