IFITM3, or Interferon-Induced Transmembrane Protein 3, is a significant component of the body’s intrinsic defense system against invading pathogens. This protein is encoded by the IFITM3 gene and acts as a cellular restriction factor. It is part of a family of proteins activated when the immune system signals a threat, playing a role in protecting individual cells from infection. IFITM3 helps establish an early barrier against various microbial threats.
IFITM3’s Role in Protecting Cells
IFITM3’s primary function involves inhibiting the entry of numerous pathogens into host cells. It achieves this by altering the properties of cellular membranes, particularly those of endosomes, which are internal compartments within cells. When viruses attempt to enter a cell, many do so by being engulfed into these endosomes. IFITM3 is strategically positioned on these membranes to interfere with the fusion process between the viral envelope and the host cell membrane.
This interference “blocks” or “restricts” invaders from successfully releasing their genetic material into the cell’s interior. By preventing this crucial step, IFITM3 ensures the viral replication cycle cannot begin, protecting the cell from infection. This mechanism makes IFITM3 a broad inhibitor, particularly effective against viruses that enter cells through endocytosis.
How IFITM3 Fights Viral Infections
IFITM3 plays a significant role in the immune response against a wide array of viruses, including influenza A virus and coronaviruses such as SARS-CoV-2. It restricts viral replication by preventing viruses from successfully entering host cells and releasing their contents into the cytoplasm. This action occurs at an early stage of infection, after the virus has bound to the cell and been internalized, but before it can begin to replicate.
For viruses that typically fuse with endosomal membranes, IFITM3 creates a barrier that prevents the formation of a full fusion pore, which is necessary for the viral genome to escape into the cell’s cytosol. This mechanism has been observed for influenza A virus, where IFITM3 allows initial lipid mixing but prevents the subsequent release of viral contents. In the context of SARS-CoV-2, IFITM3 inhibits infection by preventing virus entry, with specific regions of the protein, like its first 21 amino acids, being important for this anti-SARS-CoV-2 activity. Studies in mice have also shown that IFITM3 protects against severe SARS-CoV-2 infection by limiting viral replication and spread, which in turn reduces lung inflammation and pathology.
Genetic Variations and Health
Natural variations, or polymorphisms, within the IFITM3 gene can influence an individual’s susceptibility to severe viral infections and the resulting disease outcomes. One notable genetic variant is the rs12252-C allele, which is more common in certain populations, such as those of Chinese ancestry. Individuals who are homozygous for this C allele (CC genotype) have shown an increased risk for severe influenza virus infections, including seasonal influenza A and B, as well as avian influenza.
This genetic difference can lead to altered IFITM3 function, potentially impairing its antiviral activity and increasing the likelihood of more severe disease. For instance, the rs12252-C allele has been linked to higher mortality rates in COVID-19 patients, particularly in older individuals. While the presence of this allele does not guarantee severe outcomes, it indicates a genetic predisposition that can influence how an individual’s body responds to certain viral challenges.
IFITM3’s Broader Implications
Beyond its well-established role in direct viral defense, research suggests IFITM3 may have other functions within the body. Scientists are investigating its potential involvement in diseases such as certain cancers and possibly even bacterial infections. Studies have observed IFITM3 overexpression in various cancers, including colon, gastric, breast, prostate, lung, and liver cancers, sometimes correlating with poorer clinical outcomes.
IFITM3’s influence on cancer cells may involve regulating their proliferation, migration, and invasion, possibly by activating signaling pathways like the PI3K/Akt/mTOR pathway. It has also been shown to regulate cytokine production and immune responses, which are relevant in both infectious and non-infectious diseases. Ongoing research explores these diverse roles, aiming to uncover opportunities for therapeutic interventions or diagnostics.