Enzyme Initiates Protective Immune Responses Against Gut Parasites

NIAID Study Clarifies Role of Enzyme Previously Linked to Allergic Lung Disease

Acidic mammalian chitinase, or AMCase, an enzyme present in humans and other mammals, plays a key role in initiating protective immune responses against certain parasitic gut infections, a new NIAID study shows. The findings in mice suggest that AMCase, which had previously been implicated in allergic lung disease, is critical for defense against gastrointestinal infections with parasitic worms called helminths. The scientists report their results online in Nature Immunology on April 4, 2016.

Mammalian Chitinases: Links to Allergy and Parasite Infections

Chitinases are enzymes that break down chitin, a component of the shells and outer surfaces of insects and some parasites. Although humans and other mammals do not make chitin, they produce two chitinases—AMCase and chitotriosidase. These chitinases are thought to play a role in a specific type of immune response called type 2 immunity, which both mediates allergic inflammation and helps the body fight off parasite infections.

Past studies of AMCase largely focused on its potential role in allergic lung disease. However, researchers obtained mixed results, with some studies suggesting a key role for AMCase in allergic asthma and others suggesting that the enzyme is not involved in allergic responses in the lung. In addition, while scientists had discovered that production and activity of AMCase increases after exposure to helminths, its exact role in immune responses to these pathogens was unknown.

In the current study, investigators led by NIAID scientists Thomas Wynn, Ph.D, and Kevin Vannella, Ph.D., set out to clarify AMCase function using mouse models of parasite infections and allergy.

A Key Player in Immune Responses to Gastrointestinal Parasites

The scientists found that protective type 2 immunity following gastrointestinal helminth infections was defective in mice engineered to lack AMCase. Compared to normal mice, AMCase-deficient mice had trouble clearing infections with the helminths Nippostrongylus brasiliensis and Heligmosomoides polygyrus bakeri. These two chitin-containing parasites mature into egg-laying adults in the intestine. While N. braisiliensis migrates through the lungs on its way to the gut and causes temporary infections, H. p. bakeri is restricted to the gastrointestinal tract and can establish chronic infections. Mice lacking AMCase had a higher number of worms and took longer to expel the worms than normal mice. In addition, the AMCase-deficient mice excreted more parasite eggs.

The scientists also evaluated gene expression levels—the degree to which specific genes are turned on or off—in the infected mice. They found that AMCase-deficient mice had reduced expression of several genes involved in anti-helminth immune responses, as well as a gene involved in mucus production, which is critical for development of protective immunity against the parasites.

Photo of Heligmosomoides polygyrus bakeri infection

Heligmosomoides polygyrus bakeri infection in the small intestine of an AMCase-deficient mouse.

A Limited Role in Lung Disease

In contrast, the researchers found that the role of AMCase in allergic lung disease is limited. When exposed to house dust mite allergen, both normal and AMCase-deficient mice developed similar lung inflammation, indicating that AMCase does not influence the development of allergic lung disease.

However, exposure to the allergen increased production of AMCase in the normal mice. The scientists also found evidence that the type 2 immune response was transiently reduced in mice lacking AMCase, suggesting that the enzyme plays a role in early initiation of immune responses in the lung.

The researchers also sought to determine whether AMCase is generally required for type 2 responses to helminths by exposing mouse lungs to the eggs of Schistosoma mansoni, a parasite not known to contain chitin. S. mansoni eggs get trapped in blood vessels in the lungs, causing small areas of inflammation. Similar to their findings with house dust mite allergen, the scientists observed increased production of AMCase in normal mice in response to S. mansoni egg exposure. Both normal mice and those lacking AMCase had similar levels of inflammation, tissue thickening, and mucus production, further supporting the conclusion that AMCase is not a key regulator in the lung.

Significance and Next Steps

The researchers propose that breakdown of parasite chitin, likely in the acidic environment of the stomach where AMCase is most active, is critical for defense against certain intestinal helminths. This provides a potential explanation for why, from an evolutionary perspective, humans produce chitinases even though they do not produce chitin.

Next, the scientists plan to examine whether AMCase is important in the development of immunity to other helminths. They also are investigating the potential role of a chitinase-like protein—breast regression protein 39—in immune responses to parasites. Future studies also may assess whether chitotriosidase, the other chitinase expressed in the lung, is important in allergic airway disease.

Reference

Vannella KM, Ramalingam TR, Hart KM, de Queiroz Prado R, Sciurba J, Barron L, Borthwick LA, Smith AD, Mentink-Kane M, White S, Thompson RW, Cheever AW, Bock K, Moore I, Fitz LJ, Urban JF, Wynn TA. Acidic chitinase primes the protective immune response to gastrointestinal nematodes. Nature Immunology DOI: 10.1038/ni.3417 (2016)

Dr. Wynn's Lab