Intrinsic immunity
Encyclopedia
Intrinsic immunity refers to a set of recently discovered cellular
-based anti-viral defense mechanisms, notably genetically encoded proteins which specifically target eukaryotic retrovirus
es. Unlike adaptive and innate
immunity effectors, intrinsic immune proteins are usually expressed at a constant level, allowing a viral
infection to be halted quickly.
ary importance of fighting infection
. Some viruses, however, have proven to be so deadly or refractory to conventional immune mechanisms that specific, genetically encoded cellular defense mechanisms have evolved to combat them. Intrinsic immunity comprises cellular proteins which are always active and have evolved to block infection by specific viruses or viral taxa.
The recognition of intrinsic immunity as a potent anti-viral defense mechanism is a recent discovery and is not yet discussed in most immunology
courses or texts. Though the extent of protection intrinsic immunity affords is still unknown, it is possible that intrinsic immunity may eventually be considered a third branch of the traditionally bipartite immune system
.
s (PAMPs), triggering the expression
of nonspecific antiviral proteins. Intrinsic immune proteins, however, are specific both in virus recognition and their mechanism of viral attenuation
. Like innate immunity, however, the intrinsic immune system does not respond differently upon repeat infection by the same pathogen. Also, like adaptive immunity, intrinsic immunity is specifically tailored to a single type or class of pathogens, notably retroviruses.
Unlike adaptive and innate immunity, which must sense the infection to be turned on (and can in the case of adaptive immunity, take weeks to become effective) intrinsic immune proteins are constitutively expressed and ready to shut down infection immediately following viral entry. This is particularly important in retroviral infections since viral integration into the host genome
occurs quickly after entry and reverse transcription and is largely irreversible.
Because the production of intrinsic immune mediating proteins cannot be increased during infection, these defenses can become saturated and ineffective if a cell is infected with a high level of virus.
Other intrinsic immune proteins have been discovered which block Murine leukemia virus
(MLV), Herpes simplex virus
(HSV), and Human Cytomegalovirus (HCMV). In many cases, such as that of APOBEC3G above, viruses have evolved mechanisms for disrupting the actions of these proteins. Another example is the cellular protein Daxx, which silences viral promoters, but is degraded by an active HCMV protein early in infection.
Cell (biology)
The cell is the basic structural and functional unit of all known living organisms. It is the smallest unit of life that is classified as a living thing, and is often called the building block of life. The Alberts text discusses how the "cellular building blocks" move to shape developing embryos....
-based anti-viral defense mechanisms, notably genetically encoded proteins which specifically target eukaryotic retrovirus
Retrovirus
A retrovirus is an RNA virus that is duplicated in a host cell using the reverse transcriptase enzyme to produce DNA from its RNA genome. The DNA is then incorporated into the host's genome by an integrase enzyme. The virus thereafter replicates as part of the host cell's DNA...
es. Unlike adaptive and innate
Innate immune system
The innate immune system, also known as non-specific immune system and secondary line of defence, comprises the cells and mechanisms that defend the host from infection by other organisms in a non-specific manner...
immunity effectors, intrinsic immune proteins are usually expressed at a constant level, allowing a viral
Virus
A virus is a small infectious agent that can replicate only inside the living cells of organisms. Viruses infect all types of organisms, from animals and plants to bacteria and archaea...
infection to be halted quickly.
Background
Eukaryotic organisms have been exposed to viral infections for millions of years. The development of the innate and adaptive immune system reflects the evolutionEvolution
Evolution is any change across successive generations in the heritable characteristics of biological populations. Evolutionary processes give rise to diversity at every level of biological organisation, including species, individual organisms and molecules such as DNA and proteins.Life on Earth...
ary importance of fighting infection
Infection
An infection is the colonization of a host organism by parasite species. Infecting parasites seek to use the host's resources to reproduce, often resulting in disease...
. Some viruses, however, have proven to be so deadly or refractory to conventional immune mechanisms that specific, genetically encoded cellular defense mechanisms have evolved to combat them. Intrinsic immunity comprises cellular proteins which are always active and have evolved to block infection by specific viruses or viral taxa.
The recognition of intrinsic immunity as a potent anti-viral defense mechanism is a recent discovery and is not yet discussed in most immunology
Immunology
Immunology is a broad branch of biomedical science that covers the study of all aspects of the immune system in all organisms. It deals with the physiological functioning of the immune system in states of both health and diseases; malfunctions of the immune system in immunological disorders ; the...
courses or texts. Though the extent of protection intrinsic immunity affords is still unknown, it is possible that intrinsic immunity may eventually be considered a third branch of the traditionally bipartite immune system
Immune system
An immune system is a system of biological structures and processes within an organism that protects against disease by identifying and killing pathogens and tumor cells. It detects a wide variety of agents, from viruses to parasitic worms, and needs to distinguish them from the organism's own...
.
Relationship to the immune system
Intrinsic Immunity combines aspects of the two traditional branches of the immune system - adaptive and innate immunity – but is mechanistically distinct. Innate cellular immunity recognizes viral infection using toll-like receptors (TLRs), or pattern recognition receptors, which sense Pathogen-associated molecular patternPathogen-associated molecular pattern
Pathogen-associated molecular patterns, or PAMPs, are molecules associated with groups of pathogens, that are recognized by cells of the innate immune system. These molecules can be referred to as small molecular motifs conserved within a class of microbes...
s (PAMPs), triggering the expression
Gene expression
Gene expression is the process by which information from a gene is used in the synthesis of a functional gene product. These products are often proteins, but in non-protein coding genes such as ribosomal RNA , transfer RNA or small nuclear RNA genes, the product is a functional RNA...
of nonspecific antiviral proteins. Intrinsic immune proteins, however, are specific both in virus recognition and their mechanism of viral attenuation
Attenuation
In physics, attenuation is the gradual loss in intensity of any kind of flux through a medium. For instance, sunlight is attenuated by dark glasses, X-rays are attenuated by lead, and light and sound are attenuated by water.In electrical engineering and telecommunications, attenuation affects the...
. Like innate immunity, however, the intrinsic immune system does not respond differently upon repeat infection by the same pathogen. Also, like adaptive immunity, intrinsic immunity is specifically tailored to a single type or class of pathogens, notably retroviruses.
Unlike adaptive and innate immunity, which must sense the infection to be turned on (and can in the case of adaptive immunity, take weeks to become effective) intrinsic immune proteins are constitutively expressed and ready to shut down infection immediately following viral entry. This is particularly important in retroviral infections since viral integration into the host genome
Genome
In modern molecular biology and genetics, the genome is the entirety of an organism's hereditary information. It is encoded either in DNA or, for many types of virus, in RNA. The genome includes both the genes and the non-coding sequences of the DNA/RNA....
occurs quickly after entry and reverse transcription and is largely irreversible.
Because the production of intrinsic immune mediating proteins cannot be increased during infection, these defenses can become saturated and ineffective if a cell is infected with a high level of virus.
Activities of canonical intrinsic immune proteins
- TRIM5α (Tripartite interaction motif five, spliceRNA splicingIn molecular biology and genetics, splicing is a modification of an RNA after transcription, in which introns are removed and exons are joined. This is needed for the typical eukaryotic messenger RNA before it can be used to produce a correct protein through translation...
variant α) is one of the most studied intrinsic immune proteins due to its connection with human immunodeficiency virus (HIV) and simian immunodeficiency virusSimian immunodeficiency virusSimian immunodeficiency virus , also known as African Green Monkey virus and also as Monkey AIDS is a retrovirus able to infect at least 33 species of African primates...
(SIV). This constitutively expressed protein recognizes the capsidCapsidA capsid is the protein shell of a virus. It consists of several oligomeric structural subunits made of protein called protomers. The observable 3-dimensional morphological subunits, which may or may not correspond to individual proteins, are called capsomeres. The capsid encloses the genetic...
proteins of entering retroviruses and prevents viral uncoating and reverse transcription through an unknown mechanism. The rhesus monkey TRIM5α variant is able to recognize and prevent HIV infection, whereas the humanHumanHumans are the only living species in the Homo genus...
TRIM5α protein can prevent SIV infection. This variation helps explain why HIV and SIV infect humans and monkeys respectively, and probably reflects a previous epidemicEpidemicIn epidemiology, an epidemic , occurs when new cases of a certain disease, in a given human population, and during a given period, substantially exceed what is expected based on recent experience...
of what we now call HIV among ancestors of current rhesus monkey populations.
- APOBEC3GAPOBEC3GAPOBEC3G is a human enzyme encoded by the APOBEC3G gene that belongs to the APOBEC superfamily of proteins. This family of proteins has been suggested to play an important role in innate anti-viral immunity...
(Apolipoprotein editing complex 3 G) is another intrinsic immune protein which interferes with HIV infection. APOBEC3G is a cytidine deaminase against single stranded DNADNADeoxyribonucleic acid is a nucleic acid that contains the genetic instructions used in the development and functioning of all known living organisms . The DNA segments that carry this genetic information are called genes, but other DNA sequences have structural purposes, or are involved in...
which introduces transversionTransversionIn molecular biology, transversion refers to the substitution of a purine for a pyrimidine or vice versa. It can only be reverted by a spontaneous reversion. Because this type of mutation changes the chemical structure dramatically, the consequences of this change tend to be more drastic than those...
mutations into the HIV genome during reverse transcription by randomly changing cytidineCytidineCytidine is a nucleoside molecule that is formed when cytosine is attached to a ribose ring via a β-N1-glycosidic bond...
basepairsNucleobaseNucleobases are a group of nitrogen-based molecules that are required to form nucleotides, the basic building blocks of DNA and RNA. Nucleobases provide the molecular structure necessary for the hydrogen bonding of complementary DNA and RNA strands, and are key components in the formation of stable...
into uracilUracilUracil is one of the four nucleobases in the nucleic acid of RNA that are represented by the letters A, G, C and U. The others are adenine, cytosine, and guanine. In RNA, uracil binds to adenine via two hydrogen bonds. In DNA, the uracil nucleobase is replaced by thymine.Uracil is a common and...
. Thought this will not necessarily stop viral integration, the resulting progeny viral genomeGenomeIn modern molecular biology and genetics, the genome is the entirety of an organism's hereditary information. It is encoded either in DNA or, for many types of virus, in RNA. The genome includes both the genes and the non-coding sequences of the DNA/RNA....
s are too riddled with mutations to be viable. APOBEC3G expression is disrupted by the HIV vif protein which induces its degradation through the ubiquitinUbiquitinUbiquitin is a small regulatory protein that has been found in almost all tissues of eukaryotic organisms. Among other functions, it directs protein recycling.Ubiquitin can be attached to proteins and label them for destruction...
/proteasomeProteasomeProteasomes are very large protein complexes inside all eukaryotes and archaea, and in some bacteria. In eukaryotes, they are located in the nucleus and the cytoplasm. The main function of the proteasome is to degrade unneeded or damaged proteins by proteolysis, a chemical reaction that breaks...
system. If an HIVΔvif deletion mutant is created it will be able to infect a cell, but will produce non-viable progeny virus due to the action of APOBEC3G.
Other intrinsic immune proteins have been discovered which block Murine leukemia virus
Murine leukemia virus
The murine leukemia viruses are retroviruses named for their ability to cause cancer in murine hosts. Some MLVs may infect other vertebrates. MLVs include both exogenous and endogenous viruses...
(MLV), Herpes simplex virus
Herpes simplex virus
Herpes simplex virus 1 and 2 , also known as Human herpes virus 1 and 2 , are two members of the herpes virus family, Herpesviridae, that infect humans. Both HSV-1 and HSV-2 are ubiquitous and contagious...
(HSV), and Human Cytomegalovirus (HCMV). In many cases, such as that of APOBEC3G above, viruses have evolved mechanisms for disrupting the actions of these proteins. Another example is the cellular protein Daxx, which silences viral promoters, but is degraded by an active HCMV protein early in infection.