The Hand Lab

Unraveling the Immune Response to Intestinal Bacteria

We now understand that humans exist as a combination of host cells and a vast consortium of bacteria, viruses and fungi, called the microbiota, which overwhelm the host in number and cover our barrier surfaces. Our immune system has evolved alongside the microbiota, and the cardinal feature of adaptive immunity, “immune memory,” may be an effort to “remember” previous responses and shape subsequent host/microbial interactions. Memory immune responses form the basis of all vaccination efforts and are a critical component of immune function. However, if control over the gastrointestinal tract immune response is lost, it can lead to the development of autoinflammatory disorders.

Within the Richard King Mellon Institute for Pediatric Research, the laboratory of Timothy Hand, PhD, studies the interaction between the commensal microbiota and the immune system in the gastrointestinal tract. In particular we focus on how perturbations in the environment, such as enteric infections or changes in diet, may affect this crucial relationship. The hope is that these studies will lead to critical insights into the development of important pediatric autoinflammatory diseases such as inflammatory bowel disease and environmental enteropathy.

Areas of Focus

The bacteria that inhabit the human body are known as the commensal microbiota. These microbiota contribute to multiple aspects of host physiology and perhaps most saliently to the immune system at mucosal sites, which are directly adjacent to sites of high bacterial concentration.

The Hand Lab is focused upon two main aspects of mucosal immunity:

The latter comprises factors that lead to perturbation of the microbiome-immune relationship, including infection-induced changes, bacterial factors, nutrient-induced shifts and how these various changes in the microbiota may indicate infection and drive immune response.

Oral Vaccination

Oral vaccination can provide effective protection against infection. However, in low-income countries where oral vaccines are most vital, they have been found to be largely ineffective. Our lab seeks to identify the factors important for effective oral vaccination.

The effectiveness of vaccination depends on the development of long-lived T and B cells. Critically, for effective protection, these cells need to reside at the mucosal surfaces they aim to protect. Unfortunately the molecular and biochemical signatures necessary for survival and differentiation at these sites are unknown and therefore are a main focus of the lab.

The failure of oral vaccination in low-income countries has been associated with a chronic autoinflammatory enteropathy. We recently developed a model of enteric infection with Yersinia pseudotuberculosis that leads to chronic damage to the gut-associated lymphatics and lymph nodes, ultimately reducing the effectiveness of oral vaccination. We are planning to investigate the mechanisms of this defect and their relationship to human disease.

Immune Responses Against Commensal Bacteria

The bacteria that inhabit the gut, also known as the commensal microbiota, are of central importance to the mucosal immune response. The Hand Lab focuses on how environmental changes may strain the host/microbiota relationship. Our previous work has shown that enteric infection can significantly alter interactions between the microbiota and the host immune system. We are interested in how various perturbations, such as infection, changes in diet, etc., may affect intestinal immune responses and health long-term.

Ours and other laboratories have shown that gastrointestinal inflammation leads to the outgrowth of the Enterobacteriaceae family of bacteria. We have developed tools to study these organisms from the perspective of the immune system. However, we are also very interested in making modifications in the commensals themselves to determine the critical factors that allow for the outgrowth of these organisms and their affect on the host immune response.

It is quite clear that the changes that we have made during our evolution to a Western diet have profound consequences for the organisms inhabiting our intestines. We would like to look at how specific shifts in our diet can lead to changes to the microbiota and in particular its interaction with the host immune system.

Finally, it is now established that the immune system measures “keystone metabolites” to assess the fitness of the microbiota. We are interested in how enteric pathogens may take advantage of these metabolites to subvert the immune system to their own requirements.

Lab Team & Contact Information

Timothy W. Hand, PhD

Principal Investigator
timothy.hand@chp.edu
Read More>>

Justin Tometich
Research Technician
jut26@pitt.edu

Kathy Gopalakrishna, MBBS
Graduate Student Researcher
kpg13@pitt.edu

Contact Us

The Hand Lab
UPMC Children’s Hospital of Pittsburgh
John G. Rangos Sr. Research Center, Suite 8126
4401 Penn Avenue
Pittsburgh, PA 15224
412-692-9908

Publications

Microbiota-dependent Sequelae of Acute Infection Compromise Tissue-specific Immunity
DM Fonseca, TW Hand, S-J Han, AL Byrd, MY Gerner, A Glatman Zaretsky, OJ Harrison, AM Ortiz, M Quinones, G Trinchieri, JM Brenchley, IE Brodsky, RN Germain, GJ Randolph and Y Belkaid
Cell
2015 Oct 8

Role of the Microbiota in Immunity and Inflammation
Y Belkaid, TW Hand TW
Cell
2014 Mar 27

Intraluminal Containment of Commensal Outgrowth in the Gut during Infection-Induced Dysbiosis
MJ Molloy, N Bouladoux, JR Grainger, TW Hand, M Quinones, AK Dzutsev, J Goa, G Trinchieri, PM Murphy, Y Belkaid
Cell Host and Microbe
2013 Sep 11

Effector and Memory T cell Responses to Commensal Bacteria
Y Belkaid, N Bouladoux, TW Hand
Trends in Immunol
2013 Jun

Acute Gastrointestinal Infection Induces Long-Lived Microbiota-Specific T cell Responses
TW Hand, LM Dos Santos, N Bouladoux, A Pagan, M Pepper, CL Maynard, CO Elson, Y Belkaid
Science
2012 Sep 21

Opportunities to Join

We’d Like to Hear From You!

The Hand Lab is looking for talented post-doctoral fellows and graduate students interested in immunology, microbiology, and genetics. Please contact Dr. Hand via email if you are interested.