Pathogen-associated molecular patterns (PAMPs) are distinct molecular structures found on microbes but not in the host body. These patterns serve as a general signature, allowing the immune system to differentiate between harmful microorganisms and the body’s own cells. Recognizing these foreign patterns is a key step in initiating the body’s defense mechanisms against infection, acting as a first alert to an invading threat.
Characteristics and Examples of PAMPs
PAMPs are highly conserved molecular structures found across various classes of microbes, largely unchanged even among different species. These structures are essential for the pathogen’s survival and ability to cause disease, making them difficult for microbes to alter without compromising viability. Since these patterns are absent in human cells, they provide reliable indicators of an external threat.
Bacterial PAMPs include lipopolysaccharide (LPS), a component of the outer membrane of Gram-negative bacteria. Peptidoglycan, a major building block of bacterial cell walls found in both Gram-positive and Gram-negative bacteria, is another common PAMP. Flagellin, the protein forming bacterial flagella, and unmethylated CpG DNA sequences, more common in bacterial genomes than mammalian DNA, also serve as PAMPs.
Viral PAMPs include nucleic acids produced during replication, such as double-stranded RNA (dsRNA), unique to many viruses, or specific viral glycoproteins. Single-stranded RNA (ssRNA) from RNA viruses also functions as a PAMP. Fungi possess PAMPs within their cell walls, including zymosan, mannans, and chitin.
How PAMPs Trigger Immune Responses
The immune system detects PAMPs through specialized receptors known as Pattern Recognition Receptors (PRRs). These PRRs are expressed on various immune cells, such as macrophages, dendritic cells, and neutrophils, as well as on non-immune cells like epithelial cells. The interaction between a PAMP and its specific PRR initiates a signaling cascade within the host cell.
Different types of PRRs are located to detect various PAMPs. Toll-like Receptors (TLRs) are a family of PRRs, found both on the cell surface for extracellular PAMPs and inside endosomes for intracellular PAMPs, particularly from viruses. For instance, TLR4 recognizes bacterial LPS, while TLR3 detects viral dsRNA, and TLR7 and TLR8 recognize viral ssRNA.
Other PRRs include NOD-like Receptors (NLRs), located in the cytoplasm, which detect intracellular bacterial components like peptidoglycan. RIG-I-like Receptors (RLRs) are also cytoplasmic and recognize viral RNA, activating antiviral responses. C-type Lectin Receptors (CLRs) are surface receptors that recognize carbohydrate components found on fungi.
When a PAMP binds to a PRR, it activates intracellular signaling pathways involving adaptor molecules and kinases. This activates transcription factors like NF-κB and interferon regulatory factors (IRFs). These transcription factors move into the cell’s nucleus, inducing the production of pro-inflammatory cytokines such as TNF-α, IL-6, and IL-1β, and type I interferons.
The Role of PAMPs in Immunity
PAMP recognition serves as the initial and rapid line of defense in innate immunity. The subsequent production of pro-inflammatory cytokines and interferons orchestrates an immediate response to contain the infection.
The release of pro-inflammatory cytokines, like TNF-α and IL-6, leads to inflammation, a localized response characterized by redness, swelling, heat, and pain. This process recruits immune cells, such as neutrophils and macrophages, to the site of infection, where they work to eliminate the invading microbes. These cytokines also increase the expression of cell adhesion molecules, helping immune cells stick to blood vessel walls and migrate into infected tissues.
For viral infections, PAMP-induced signaling activates the production of type I interferons (IFN-α and IFN-β). These interferons establish an antiviral state in infected and surrounding cells, inhibiting viral replication and spread. This involves inducing genes that directly interfere with various stages of the viral life cycle.
Beyond innate immunity, PAMP recognition also plays a role in activating the adaptive immune system, which provides a more specific and long-lasting defense. PAMP-induced signals promote the maturation of antigen-presenting cells (APCs), such as dendritic cells. These mature APCs then travel to lymph nodes, where they present pathogen-derived antigens to T and B lymphocytes, thereby initiating a targeted adaptive immune response. Without this initial PAMP-driven alert, the adaptive immune system might not be effectively primed to respond to the specific threat.
While PAMPs alert the immune system to external microbial threats, the body also recognizes internal danger signals released from damaged host cells, known as Danger-Associated Molecular Patterns (DAMPs). Both PAMPs and DAMPs bind to PRRs, triggering inflammatory responses, but PAMPs specifically indicate infection, whereas DAMPs signal internal tissue damage or stress.