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UMass Chan researchers show immune response to Salmonella requires specific combination of cells

Study provides a more nuanced understanding of how the immune system responds to enteric infections

Milena Bogunovic, MD, PhD

Research from the lab of Milena Bogunovic, MD, PhD, associate professor of pathology, shows that a specific combination of cells is necessary for the activation, initiation and control of immune responses to infection in the intestine. Published in Science Immunology, the study found that a certain subtype of macrophage (white blood cells that engulf foreign or infective bodies) present in the intestine induce activation of protective Immunoglobulin A (IgA) antibodies in response to Salmonella infection. A better understanding of how the immune systems responds to enteric infections such as Salmonella, and other bacteria, is critical to the development of vaccines for illnesses that are becoming increasingly resistant to standard antibiotics.

“These findings enhance our knowledge of the functional diversification of the macrophage subsets associated with Salmonella infection and colonic inflammation,” said Dr. Bogunovic. “Given the rise of antibiotic-resistant Salmonella strains and in the absence of vaccines, there is a growing need to increase our understanding of immune responses to Salmonella infection so we can develop new and more efficient interventions.”

Salmonella enterica is a gram-negative bacterium with a rod-shaped appearance. Mostly known as a food-borne pathogen, Salmonella causes millions of cases of gastroenteritis every year, with Salmonella gastroenteritis being a risk factor for inflammatory bowel disease. More serious forms of the Salmonella bacteria are responsible for typhoid fever and paratyphoid fever.

Although a lot is known about the role dendritic and macrophage cells play in a normal and healthy intestine, not much is known about the population, composition and function of these cells when the intestine is in an inflammatory state.

By using a combination of phenotyping, transcriptional and functional analysis to examine the complexity of the inflammatory myeloid cells that infiltrate the Salmonella infected intestine, the Bogunovic lab found that a heterogeneous group of CX3CR1+ macrophages was necessary for the induction of a protective IgA response to Salmonella. The IgA antibody plays a crucial role in the immune function of mucous membranes, like those found in the intestinal linings. Because the main known function of macrophages is regulation of inflammation, finding that these cells were inducing Salmonella-protective IgA antibodies and were superior to their dendritic cell counterparts in doing that was unexpected.

One of the particular macrophage subsets was required to form tertiary lymphoid structures that developed at sites of Salmonella invasion. These abnormal lymph node-like structures form in peripheral tissues at sites of chronic inflammation and cancer and are regulated differently than normal lymphoid tissues. Although the exact function of tertiary lymphoid structures remains elusive, recent studies suggested their involvement in disease pathophysiology. The Bogunovic lab found that these structures assume an immune role during the inflammatory process by contributing to induction of localized IgA antibody responses to Salmonella through production of a unique combination of cytokines such as CXCL13, TGF-beta1 and IL-10.

“These findings enhance our understanding of the functional diversification of the macrophage subsets associated with Salmonella infection and colonic inflammation,” said Bogunovic. “Collectively, our study closed a knowledge gap in our understanding of the mechanisms used by macrophages and dendritic cells to contain infection.”

Several anti-inflammatory therapies for inflammatory bowel disease that are either FDA–approved or in Phase 2 and 3 clinical trials, target macrophage function by neutralizing cytokines that they produce or by blocking their signaling pathways, although these therapies also lead to immunosuppression and the increased potential for opportunistic infections. This study provides the foundation for future studies to develop more sophisticated approaches for therapies of inflammatory bowel disease.