Infectious disease is one of the largest killers of all organisms, with large organisms falling prey to smaller organisms and smaller organisms falling prey to micro organisms, the ability to protect one's self during an assault from a foreign invader is mandatory for an organism to mature and reproduce (Rolff and Siva-Jothy, 2003). Vertebrates and invertebrates have established different mechanisms of protection against infection and disease, with some developing complex and partly organ based systems of immunity.
Immunity in vertebrates is classified into two components:- innate and adaptive. Other classifications are available, for example cellular and humoural. Innate immunity refers to the inherited immune system of primary defences conferred to the organism by the parent during development (Hoffmann and Reichhart, 2002); it is rapid (i.e. an immediate response) and evolutionarily older than adaptive immunity. Adaptive immunity refers to the acquired immune system, based on past experience (including pathogen burden) or actual antigen memory. It is complex and (in vertebrates) is driven by variation in T-cell receptors and major histocompatibility complexes produced by differential mRNA processing after gene transcription, recombination and alternative splicing of genes (Jung and Alt, 2004). The main function of adaptive immunity is to produce a library of all the cell surface recognition proteins experience by the individual in order to decrease response times when producing a specific response upon secondary exposure.
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The opposite can be said for invertebrates as in a large proportion of invertebrates there is no evidence of an adaptive immune system but they still thrive in pathogen rich environments (Boman, 1998), an example of this would be insects; insects are able to overcome infection from a number of different organisms, from bacteria to fungi, protists, nematodes and even viruses and although the mechanisms for fighting off these pathogens are not necessarily specific to the pathogen or the potential host they are still nevertheless effective (Siva-Jothy et al, 2009).
Insect immune systems do share similarities with vertebrate immunity however, insect haemocytes being cells that carry out functions similar to white blood cells, and found in the circulatory system (haemolymph) where they mediate phagocytosis in a similar fashion to macrophages. Another parallel is the prophenoloxidase cascade this is a wound response cascade that is similar to the complement cascade in humans; both cascades work to clot wounds and trap any pathogens close to the site of infection(reference).
Immune responses in Insects
Insect immune systems are made up of a variety of components; firstly the defence organs, consisting of physical barriers that work to prevent the entry or proliferation of pathogens in the host body, an example of such organs is the waxy cuticle, immunosurveillance proteins - that monitor the haemocoel for any foreign antigens - studies have shown the epidermal epithelium to be a critical component in the detection of pathogens, results suggest the basal lamina (Fig 1) provides a norm for which immunosurveillance proteins can compare antigens against to determine whether they are self or non-self (Liu et al, 1998).
The importance of physical barriers is to compartmentalise the body into distinct sections blocking entrance to internal cavities except through tightly guarded entrances and exits. This body design confers three major benefits; firstly the physical barriers restrict the movement of any pathogens present thereby reducing the area that the pathogen can get to, secondly compartmentalisation makes it possible for the immune system to deliver a highly concentrated immune response to a localised area increasing the likelihood that effector cells will come into contact with and overcome the pathogen (Hoffman and Reichart., 2002). Thirdly by constricting the access points of pathogens to the alimentary canal, once infections are stopped they can easily be eliminated from the body.
Upon contact with a pathogen, the first and most important line of defence is the waxy cuticle. The cuticle is the outer most tissue of an insect, secreted by basal epidermal cells, it is made up of three distinct sections; the epicuticle, the procuticle and the inner epithelial cells, each layer has different properties that combine to give insects a substantial protection from infection. Other physical barriers that provide protection against pathogens include the gut wall and the reproductive tract which in insects is lined with a chitinous membrane or a cuticle (reference).
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Recognition of a pathogen depends on how efficient an organism's immune system is at distinguishing between self and non-self antigens - small peptides present on the extracellular membrane - each organism has its own unique antigens and the further derived from the species the one organism is to another, the more different the antigens are* Insect recognition of microbial pathogens is an area of interest for many, as gaining a better understanding of these processes would help to create a strategy to control the growth of termites in environments where they are seen as pests, such as in farming communities where they consume crops (Su and Scheffrahn, 1998). The insect response to a microbial threat occurs in one of four ways; activation of the prophenoloxidase cascade, induction of anti microbial proteins (AMPs), phagocytosis and encapsulation. (Siva-Jothy et al, 2009), performing any number of these processes in response to a pathogen. Two main pathways have been noted as being instrumental in insect immunity, the Toll and Imd pathways, activated by different antigens they initiate the transcription of genes that fight pathogen infection.
It can therefore be said that insect immune systems favour a rapid non-specific response as opposed to a response tailored to the immunogen, taking advantage of the short response times needed for the innate pathway to operate.
Termites as a model for insects
Termites exhibit various traits that make them an ideal model order (Isoptera) for research in insect immunity as they display many core features that are ubiquitous among the insect family. Termites are subterranean insects that live in warm soils in high density, ranging from a few hundred to a million individuals, feeding on decomposing inorganic materials including wood, humus, lichens and other detritus and living in the surrounding environment; these lifestyle behaviours mean that they are constantly in an environment that aids the proliferation of microbial organisms this eusociality provides an interesting insight to the workings of pathogen activity in colonies, different termite species have different microbial loads, comparisons between these species may help to gain a clearer understanding of immune responses to host specific pathogens and the evolution of increased immunity against a certain pathogen (Calleri et al, 2010), termites are coelomates with open body cavities filled with fluid called haemolymph, haemolymph allows nutrients to easily diffuse to different regions in the body however this can also have a converse effect as pathogens are able to disuse easily through haemolymph.
Immune challenges of termites (hygiene in social systems; energetic costs of immunity)
As many species of termites reside in densely populated environments, the likelihood of an infectious disease being transmitted from one individual to another is expected to be quite high in relation to a population that has few individuals but the same area of land. This however was not observed when looking at dampwood termites. Studies in Zootermopsis angusticollis have shown immune responses to a pathogen to be significantly faster in termites in groups when compared with termites placed in isolation, suggesting that sociality confers some benefits to disease resistance (Ugelvig and Cremer, 2007). Rosengaus 1998 states that termites in colonies modify their behaviours in response to pathogens present and that the hazard ration of termites in colonies versus termites in isolation can be up to 83% lower in termites in a colony.
Examples of experimental methods
Experiments have indicated that there is a cost for maintaining immune defence levels; this is shown by regulation of immune responses, if there was little or no cost then it would make sense for immune responses to be similar at all times, however this was not the case. Upregulation and downregulation of the immune response tells us that immunocompetence has a cost and that there are times when the cost of immunity comes into conflict with other necessary life processes such as during the metamorphosis of hemimetablous insects (Thomas and Rudolf, 2010) where pathogenic assault during development was shown to increase the rate of mortality in insect larvae. Calleri et al (2006), describes how Metarhizium anisopliae (a microbe that is pathogenous to termites), is used to determine whether infection reduces survival and fitness in Z. angusticollis
Case: mated reproductive primaries, control - non mated primaries. Exposure to parasites leading to increased protection in subsequent challenges.
What can be used to test pathogen responses?
The Cellular and Humoral response
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The cellular immune response to disease and infection is mediated by effector cells called haemocytes, performing three main tasks; phagocytosis, encapsulation and activation of the prophenol oxidase cascade. Phagocytosis is the facilitated endocytosis of foreign bodies or diseased cells that are smaller than a haemocyte, once the pathogen is engulfed it is broken down by catalytic enzymes such as lysozyme or Reactive Oxygen Species (Gupta et al, 1991). Increased rates of phagocytosis have been detected upon introduction of cyclic AMP suggesting that the adenylyl cyclase system is involved in the act of phagocytosis (Bains and Downer, 1992) however there is little understanding as to why. Encapsulation occurs when a cell is too large to be engulfed by a single haemocyte, multiple haemocytes
prophenol oxidase cascade
Wound responses - melanisation. synthesised in the haemocytes (Brey and Ashida 1995)
Cellular--- localised amps at high concentrations due to body compartments
Known immune responses by pathogen group
Each organism has a specific signature, this signature presents itself as small glycoproteins on the cell membrane of almost every cell and is called an antigen, special proteins in the immune system read these antigens to detect whether they are from the organism or not; if they are endogenous to the organism they are called self antigens and those that are not are called non self antigens. If a non self antigen is detected this usually leads to an immune response that culminates in the host destroying and expelling the foreign body. Response to a pathogen largely depends on the events that occur during the initial interactions between the immunosurveillance proteins that circulate the host body and pathogens; these surveillance proteins or pattern recognition receptors (PRRs) have evolved over time to recognise specific glycoproteins that are unique in pathogenic microorganism antigens producing shorter response times these unique proteins are called pattern-associated molecular patterns or PAMPs (Gillespie and Kanost 1977). The role of PRRs is to activate a specific immune response to a threat, signalling transduction for immune responses.
Foreign antigens do not always illicit an immune response, in many organisms there are non self antigens that are present such as bacterial or eukaryotic microorganisms that live in symbiosis with termites (Bignell, 2000). In such cases an immune system has to constantly regulate its efficiency to balance the benefits gained from endosymbiotic protozoa against the potential risk of infection, this is called tolerance; if an immune system is very tolerant to non self antigens, pathogens that enter have a higher likelihood of proliferating however if tolerance is non-existent this would lead to all non self antigens, beneficial and harmful eliciting an immune response and in some cases this could even lead to the immune system attacking self antigens. In 2006 Laidman-Remy et al, detailed how some endosymbionts express low levels of peptidoglycan on their cell walls however they do not illicit an immune response, it is possible that there is a threshold for peptidoglycan expression that once expressed illicits an immune response and that endosymbionts do not exceed it. There are four main classes of organisms that act as pathogens against insects: bacteria, fungi, nematodes and viruses each of which shall be looked at in detail.
Insects are susceptible to a wide range of bacteria such as Serratia marcescens or Bacillus thuringiensis , ants secrete an antimicrobial compound as a primary barrier against bacterial pathogens so bacteria normally enter through the alimentary tract and then spread to the haemocoel however upon infection the presence of pathogenic bacteria in the insect immune system illicits an immune response; mediated by protein recognition receptors, antigens present on the surface of bacterial cells namely peptidoglycan and lipopolysaccharide are recognised by Gram-negative bacteria binding proteins such as GNBP2.
Conformational changes in GNBPS initiate the transduction of information regarding the pathogen causing the induction of AMPs this is called the Imd pathway and is activated mainly in the presence of Gram-negative bacteria. Once the Imd pathway is activated, Relish, a transcription factor present in a bound state in the cytoplasm of fat body cells is phosphorylated and translocated to the nucleus in order to initiate transcription of AMPs. These various AMPs work in a number of ways from cecropins that disrupt the synthesis of bacterial proteins required to make the membrane thus inhibiting growth to defensins that cause lysis as seen in Phormia terrranovae (Cociancich et al, 1993) as well as a host of others such as attacins and diptericin that have similar functions against bacterial cells.
It is not fully understood how Relish is cleaved however analysis of homologous mammalian proteins IB kinase β indicates that the genes responsible must be closely related as Drosophila knockouts of genes with similar sequences have shown an inability to initiate the Toll Pathway (Hoffmann and Reichart, 2002).
Termites live in microbially rich environments, some entomopathogenic fungi such as M. anisopliae that grow in conidia form attach to and colonise the cuticle surface of termites and utilise catalytic enzymes to corrode the cuticle (Charnley and St. Leger, 1991), they then enter the haemocoel where they quickly multiply by budding or fission other entomopathogenic fungi however such as Beauveria bassiana enter the termite system through the alimentary tract.
There are two important prophylactic measures to counter fungal infection that should be noted. Firstly the secretion of defensin-esque proteins on the cuticle called termicin by termites. The epicuticle is the outer layer of the cuticle, being very thin it was not thought to confer any substantial protection against pathogens however new studies have shown that in Nasutitermes triodine antimicrobial activity occurs as a product of secretions by the prefrontal adrenal gland. The second measure is cuticle thickness; this could be seen as an adaptation response to fungi that attack the cuticle (Hajek and St. Leger, 1994), the procuticle, consisting of the endocuticle and exocuticle, is the thickest and second most outer layer, gaining its thickness and strength from melanisation.
Fig. 1 The structure of the insect integument (modified from http://www.nazarian.ir/biodb/en/insects_anatomy.asp).
Upon fungal infection of the termite immune system, pattern recognition receptors that circulate the insect haemocoel and tissue detect β 1,3 gluccans and β 1,3- mannans in fungal cell and signal the activation of the Toll pathway.
Toll is a receptor that initiates the immune response for fungi and Gram positive bacteria it is activated when the ligand, Spätzle is bound to it, once activated, Toll activates the protein Kinase Pelle using the intracellular Toll/interleukin-1 receptor domain. Kinase Pelle causes the translocation of Relish transcription factors Dif and Dorsal to the nucleus by degrading an inhibitor protein called Cactus; Cactus binds Dif and Dorsal in the cytoplasm, once translocation occurs the factors enter the nucleus and binds to enhancers regions to promote transcription of AMP genes effective in combating fungal infection such as drosomycin, heliomycin and Metchnikowin (Fehlbaum et al, 1994). Defect experiments show us that Drosophila Spätzle mutants are still capable of producing a Toll pathway immune response which tells us that although Spätzle is the only known ligand for Toll receptor activation, there are other ways the receptor can be activated (Lemaitre et al, 1995).
Response: systemic and
Termites also produce AMPs such as norharmane, isolated from Reticulitermes sp, norharmane is ubiquitous in plants and some animal taxa and is produced by endosymbionts that reside in the mid-gut of termites (Chouvenc et al, 2009). The role of norharmane is to inhibit the germination of infectious fungi it is involved in the non cellular immune response to pathogens (Rosengaus et al, 98, 2000).
Nematodes are obligate parasites of insects commonly found in soil, they inhabit similar environments to dampwood termites as they are attracted to detritus such as decaying wood, (Imaz et al., 2002) which termites use to make nests. Organisms such as Steinernema carpcapsae act as Entomopathogenic Nematodes (EPNS) to insects, nematodes usually enter through the alimentary tract however Mermithidae have been observed to enter via the cuticle. Entomopathogenic nematodes are larger than other insect pathogens and often are in symbiosis with bacteria called enterobacteriaceae, upon entering the homocoel nematodes release these highly virulent bacteria (Dowds et al, 2002).
Wilson-Rich et al, 2007 describes possible immune responses in Z. angusticollis that may be specific to EPNS infection; among 15 behavioural traits that were observed before and after nematode infection, six novel traits were seen to significantly increase in frequency these traits are allogrooming, self grooming, vibratory displays, chewing, abdominal tip raising and scratching
It is thought that these behaviours are effective in combating nematode infection.
Unlike insect responses to bacterial, fungi and nematodal pathogens not a lot is known about insect responses to viral pathogens, however early studies have shown two distinct mechanisms that are used in the insect immune response; RNA silencing and inducible responses. RNA silencing is the targeting and cleavage of double stranded RNAs (dsRNA) by small interfering RNAs, the exogenous viral RNA bound by an effector protein that signals the protein Dicer to cleave the dsRNA, this effector protein has been isolated in D.melanogaster and is called R2D2, it activates upon viral entry into the cell cytoplasm. (Li et al., 2004)
Although it is unclear as to how specifically responses to viral pathogens act, studies of mRNA transcript expression have indicated that an induced response does in fact take place. Observations of the presence of pre mRNA transcripts before and after injection of D. melanogaster with the virus () shows a significant increase in specific genes such as () these genes are thought to combat viral pathogens.
melanisation, this is the process of
Mechanisms of immunology: molecular, chemical, behavioural, physical
Insects have been shown to obtain protection from pathogens through behavioural traits, these behaviours fall into two classes; responsive and prophylactic, encompassing such behaviours as grooming, alarm behaviours and avoidance of cadavers. Physical - Prophylactic measures such as thick cuticles etc
In some species of termites (genus species) it has been noted that during times of nutrient scarcity, the cannibalism of dead or dying individuals takes place in order to survive, although this drastic measure of survival provides nutrition, it has been observed that cannibalism of an infected individual can spread disease. Conversely trophallaxis is a hygienic behaviour in which fluid is passed from one organism to another via the buccal cavity, this practice is ubiquitous in social insects such as Bombus terrestris and Incistermes schwarzi. The act of trophallaxis has been seen to lower rates of disease (reference).
Initial contact between AMPS and bacteria is electrostatic (et al,. neuroscience ref ); bacteria have anionic membranes and anti bacterial proteins have cationic membranes, this attribute must have arisen and been highly successful so become fixed in the gene pool. Role of cAMP in immune response regulation.
Development of immunities during termite development (variations with age and caste)
Inter and Intra specific variation in termites producing differences in susceptibility to pathogens in a species and between species.
Hemimetabolous organisms inhabit separate habitats; less competition between life stages, different resources mean different microbes meaning different pathogens/immune pressures.
Genetic basis of immunity
Protein induction occurs after signals are transmitted to the nucleus of fat body (and some haemocyte cells (ref)) to up regulate transcription of AMP genes such as diptericin and cecropins, that are tran.
In humans, adaptive immunity is driven by genetic recombination of V (D) J regions and T Cell receptors, creating diversity and specificity, not the case for invertebrates.
Transposable elements are sections of DNA that have to ability to move from one position in the genome to another or multiply themselves and introduce the clones back into the genome. Transposition can be viewed as a mechanism for creating genetic diversity; upon moving or reinsertion into the DNA sequence these mutations may interrupt or initiate genes transcription machinery creating mutants that may have an increased susceptibility to infection or a faster immune response. Studies have shown that retroposons increase transposition frequency in response to stress from the host (professor Malcom), as this only occurs in the germ line this mutation could be passed onto offspring and confer more efficient microbial resistance mechanisms in later generations.
Population genetics of immunity and termite breeding behaviour
There are various factors that determine the immunocompetence within a population such as mineral resources; nitrogen availability has been proven to be a limiting factor in immune responses this is because nitrogen is needed to synthesis various antimicrobial proteins essential for immunity. Pathogen diversity can also
Pathogen life cycles have also been seen to influence immunocompetence, pathogens that have
In the Bombus terrestris, prevalent pathogen infection in one generation has been noted cause an upregulation of PO enzyme activity in the next generation (Sadd and Shmid-Hampel, 2006).
Outbreeding could be hazardous because immune genes may be lost i.e. difference in prefrontal adrenal gland between species; gland has role in prophylaxis (Sobotnik et al, 2010).
Toll pathway stimulated by presence of sex peptide (injury during mating lead to infection etc)
Studies show that the genes responsible for the creation of the Toll and Imd pathways are highly conserved in insect with orthologues detected in drosophila, mosquitoes and bees (Zackton et al., 2007; Zou et al., 2007 and Waterhouse et al., 2007).
that the flies injected during the night are better
able to clear the bacteria, suggesting that circadian
rhythm alters the resistance to these microbes.
Rosengaus and Tranielli (1993) stated that an important factor in evolution is disease resistance, noting that sexual selection for disease resistance combined with increased fitness work to increase these beneficial alleles in insect populations.
The defence component model; parasite-host relationships and its effect on the evolution of insect immune systems.
It has been considered that the reason many insects do not have an adaptive immune system could possibly be due to the life span of the hosts; as many insects live short life spans some as little as a few days, so when the likelihood of coming into contact with the same pathogen is so small the need to invest in a biological system that requires energy is minimal.
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