The Aderem laboratory consists of researchers from a variety of fields, who are dedicated to studying the biology of the macrophage and its functions in disease. A large portion of the lab is focused on understanding Toll-like receptor (TLR) functions in innate immunity.
The lab is committed to applying a systems biology approach to these host-pathogen interactions. The innate immune system is responsible for defense in the first hours of an encounter with a potential pathogen. It has been trained over millions of years of evolution to recognize invaders and evoke potent anti-microbial responses aimed at killing microbes before they become a threat to the person.
The laboratory is particularly interested in the mechanisms whereby these alarm signals are generated. The 12 members of the Toll-like receptor (TLR) family perform a critical role in this signaling and are detected at the sites where microbes are engulfed by macrophages (see Figure 1). TLRs are able to recognize many different features of microbes, primarily combinations of sugar, protein, and lipid components of microbial cell walls, as well as toxins, metabolites, and even microbial nucleic acids (see Figure 2). These structural features mostly are not found normally in human tissues and thus allow discrimination of self (the human host) from non-self (the microbe).
One unifying feature of these targets is that they all perform functions essential for the life or pathogenicity of the organisms. Thus, they possess conserved structural motifs that are not easily altered by the microbe to evade detection. TLRs are part of an ancient defense mechanism against microbes that is used by many organisms (humans, mice, flies and even plants) to specifically detect the presence of invading microbes. Studies on TLRs have shown how a limited set of germ-line encoded receptors (fixed in our genes) is able to participate in the perception of a wide variety of pathogens, including organisms as diverse as Gram-positive bacteria, Gram-negative bacteria, mycobacteria, yeasts, parasites and viruses.
The functions of eight of the twelve members of the TLR family reveal that macrophages utilize different TLRs to detect different microbial components (see Figure 3). One interesting feature of TLR activation is that certain TLRs function together in order to recognize different microbial components and to signal. For example, TLR2 is able to recognize different microbial products when paired with TLR1 or TLR6. At another level, TLRs cooperate with each other by being activated in parallel during encounters with microbes. Thus, different TLRs simultaneously recognize different sets of components present on the surface of a given pathogen (see Figure 4). In this manner, a diverse spectrum of pathogens is detected. Furthermore, the specificity of TLR recognition permits the inflammatory response to be tailored to eliminate particular pathogens.
TLRs and other microbe-recognition receptors initiate signaling in phagocytes that lead to inflammatory responses specific to the type of pathogen encountered. Our laboratory is helping to define these signaling pathways and to model the complex interactions that lead to specific responses. The responses are complicated as the expression of thousands of different genes are altered in response to TLR signaling (see Figure 5).
A growing number of receptors have been identified that can generate signals leading to phagocytosis. Some receptors such as Fc-receptors and complement receptors recognize particles that become coated with antibodies or complement in the serum. Other phagocytic receptors such as the mannose receptor recognize microbes directly. These receptors each trigger phagocytosis in slightly different ways, and the inflammatory consequences of stimulation through different phagocytic receptors vary. Thus, the mechanism of phagocytosis is extremely complex, and no single model can fully account for the diverse structures and outcomes associated with particle internalization.
The Aderem Lab has made important contributions to the understanding of the molecular mechanisms underlying phagocytosis. We believe that the complexity of phagocytosis must be embraced in order to really understand the interactions of multiple receptors, interwoven signaling pathways, and the capacity of microbes to influence their fate as they are internalized.
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