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REVIEW ARTICLE Chicken Infectious Anemia: An Emerging Immunosuppressive Viral Threat to the Poultry Industry

B.P. Kamdi 1* , R.P. Kolhe 2, V.S. Dhaygude 1 and C.S. Mote 1

1* Department of Veterinary Pathology, 2Department of Veterinary Public Health, KNP College of Veterinary Science Shirwal, District-Satara, 412801, India.

Abstract Chicken infectious anemia (CIA) is a very important disease of chickens with worldwide distribution. It is accountable for the huge economic losses to farmers rearing chickens. Chicken infectious anemia (CIAV) belongs to the genus from the family. It can affect all the age group of chickens, but clinical disease is most commonly encountered in birds aging 2-3 weeks old. Infection of birds older than 3 or 4 weeks of age does not cause clinical disease but can * Corresponding Author: lead to immunosuppression, resulting in secondary infection and failure. CIAV characteristically transfers through horizontal as B.P. Kamdi well as vertical route of transmission; vertical transmission being most Email: [email protected] significant. Marked aplastic anemia, moderate to severe atrophy of the , atrophy of the , muscular hemorrhages, Received: 19/02/2020 immunosuppression and less commonly atrophy of bursa of Fabricius are Accepted: 25/03/2020 characteristic findings in the CIA affected birds. CIAV considered to be of no public health significance and chicken being the only natural host for the virus. However, recent reports about the isolation of CIAV and closely related gyroviruses from the healthy as well as diseased individuals suggest its potential threat to the human population. CIA can be tentatively diagnosed from typical clinical signs and lesions, but to confirm the CIAV infection various laboratory tests are used. As there is no specific treatment for the disease, breeder vaccination, biosecurity and preventive measures are of utmost importance to control the disease.

Keywords : Epidemiology, Chicken Infectious Anemia, Immunosuppression, Vertical transmission.

1. Introduction threatening the poultry industry. Specifically, Poultry production is one of the important immunosuppressive viral infections like Chicken sectors in the agriculture industry with a rapid growth infectious anemia (CIA), Marek’s Disease (MD), vis-a-vise other agriculture sectors. Once poultry Infectious Bursal Disease (IBD) and Reo viral farming was considered as a backyard venture, infections are of enormous significance due to their however, in the recent years it has transferred to strong immunosuppressive nature, resulting in vaccine failure agro-based farming activity. It provides an employment and predisposing the birds to various secondary and livelihood to the large number of marginal farmers infectious agents. CIA is an economically important in the developing countries. A multifold growth of the avian disease and ubiquitous in flocks all over the poultry industry with an intensive rearing system world. It (CIAV, Gifu -1 strain) was first isolated in resulted in the increase in prevalence of many Japan in the year 1979 by Yuasa and coworkers (Yuasa infectious diseases which are responsible for heavy et al., 1979). It is characterized by aplastic anemia and economic losses. Economic losses are due to mortality, thymic atrophy and subsequent immunosuppression. It decreased production and increased treatment cost. The is regularly associated with other diseases, such as intensive rearing system of birds with a high density of necrotic dermatitis, hemorrhagic syndrome, aplastic poultry population has contributed to the survival of anemia syndrome, and blue wing disease as a different infectious agents in the endemic area. In consequent of immunosuppression. The disease is addition, to increase the profit, continuous production frequently complicated by secondary viral, bacterial or stress over birds to produce or to gain maximum fungal infections (Orakpoghenor, 2019). The disease weight, lead to metabolic derangement with a poses a serious threat to the poultry industry and the consequence of increased susceptibility to various producers of the specific pathogen-free eggs. In India, infections. Thus, various viral diseases which are of the CIA has been suspected since long on the basis of most significance are resulted in huge mortality and clinical signs and lesions in the major poultry raising

Journal of Poultry Science and Technology | January-March, 2020 | Volume 08 | Issue 01 | Pages 16-22 © 2020 Jakraya Kamdi et al...Chicken Infectious Anemia: An Emerging Immunosuppressive Viral Threat to the Poultry Industry

states of the country (Verma et al., 1981; Suresh et al., VP1 is essential for the pathogenesis of CIAV. The 1995). Venugopalan et al. (1994) reported the disease substitution of one amino acid in three cloned by demonstrating CIAV by immunoperoxidase test could alter the pathogenicity of the virus distinctly. while investigating an outbreak of multifactorial When the amino acid glutamine was substituted, the etiology in young growing chickens in the poultry belt virus showed high pathogenicity while substitution of of Namakkal (Tamil Nadu). Kataria et al. (1999) histidine lowered downs the pathogenicity of CIAV reported the existence of the CIA in three states (Tamil (Yamaguchi et al., 2001; Eltahir et al., 2011). Nadu, Maharashtra and U.P.) in India by PCR detection Interestingly, VP3 was found to induce apoptosis in of CIAV-DNA in the clinical samples and carried out several malignant lymphoblastoid cell lines and human transmission study in chicks. Over the period of time, osteosarcoma cells but not in normal human cells the disease has been reported from multiple locations (Schat, 2009). The oncolytic properties VP3 protein throughout India (Dhama et al., 2002; Verma et al., needs to explore in more detail so that it can be one of 2005; Natesan et al., 2006; Praveen et al., 2008; Kamdi the alternatives in the cancer treatment. et al., 2015; Ganar et al., 2017). The emergence of CIA is posing a severe threat to the Indian poultry industry. 3. Public Health Significance The present review provides information about the CIA Until recently CIAV was considered as a sole in brief. member of the Gyrovirus genus. Most commonly reported from chicken and considered of no public 2. The Virus health significance. But, recent reports of ‘Human CIAV is the smallest DNA virus, currently Gyrovirus’ (HGyV) from the human skin surface classified in the Anelloviridae family and Gyrovirus showing homology with CIAV (Sauvage et al., 2011) genus (Rosario et al., 2017; ICTV, 2018). Earlier it was doubts its infectivity for human tissues. Furthermore, in classified in a Circoviridae family, but significant 2012 two Gyrovirus (GyV3 and GyV4) were identified differences in genome organization led to its from the fecal samples of human consuming CIAV reclassification into the new Anelloviridae family. It is infected and/or vaccinated chickens (Phan et al., 2012; a small non-enveloped virus that is resistant to thermal Zhang et al., 2012). CIAV shows many similarities inactivation, lipid solvents and many of the commonly with these human gyroviruses. Smuts (2014) used disinfectants. The genome is a circular single demonstrated the presence of CIAV and related negative-stranded DNA, covalently linked and consists gyroviruses in the South African human population of about 2319 nucleotides. The virus has icosahedral with diarrhea, respiratory illness and some healthy symmetry with an average diameter of 23-25 nm individuals. CIAV has also been detected from the (Orakpoghenor, 2019) and replicates through the feces of mice and dogs (Fatoba and Adeleka, 2019). rolling circle model (Meehan et al., 1992). There is Such instances indicate the potential ability of CIAV to only one recognized serotype of CAV at this time; threaten human health. however, there have been reports for several years of different pathogenosities between CAV strains, but 4. Transmission of CIAV they are all still recognized as one serotype (Spackman CIAV has been reported to be transmitted et al., 2002). The CAV genome has negative-sense horizontally and vertically (Yuasa, 1991; Li et al. , single-stranded DNA with one promoter-enhancer 2017). Horizontal transmission by direct and indirect region. CIAV has three partially overlapping open contact most often occurs via oral route, because very reading frames (ORFs), encoding for three viral high concentrations of virus particles are excreted in proteins (VP1, VP2 and VP3) through the use of the feces of infected birds (Maclachlan and Dubovi, alternate start codons (Noteborn et al., 1991). VP1 2017). In the field conditions, close contact of birds (51.6 kDa) is the major structural protein found in the allows CIAV transmission by the respiratory route and capsid and associated with virulence, cell infecting infected feather follicle epithelium. Other horizontal ability and virus replication. The non-structural protein means of transmission such as contact and/or exposure VP2 (24 kDa) has been shown to have protein to contaminated litter and fomites have been reported phosphatase activity and has a role in capsid formation (Schat, 2009). The most important means of such as a scaffold during virion assembly for proper dissemination of the virus has been suggested to be by folding of VP1. Both VP1 and VP2 proteins are vertical transmission through hatching eggs (Smith et required to induce protective , the absence of al., 1993; Snoeck et al., 2012) and this happens when either of VP1 or VP2 fails to induce neutralizing sero-negative hens contract infection through horizontal antibodies (Koch et al., 1995). Certain mutations in the route; this continues until an adequate level of virus VP2 alter its phosphatase activity results in attenuation protective antibody develops in hen. Vertical of virus replication. VP3 (13.6 kDa) also known as transmission can occur for a period of 3-9 weeks apoptin causes apoptosis in chicken thymocytes and following exposure to CIAV (Maclachlan and Dubovi, chicken lymphoblastoid cell lines and has recently been 2017). CIAV present in the semen from an infected shown to bind to cellular DNA (Miller et al., 2005; rooster and it can be another source for vertical Dhama, 2008). The single amino acid at position 394 in transmission. Vertically infected chicks spread virus

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horizontally to maternal antibody-negative hatch mates CIAV infection (Smith et al., 1993). Interference of more efficiently. CIAV infection with the transcription of cytokines such as interferon also found to contribute to the 5. Host and Cellular Tropism of CIAV pathogenesis of the disease. The clinical disease mostly The chicken has been reported to be the natural noticed in the 2 to 3 weeks old chickens; however, host for CIAV infection and all the age group chickens CIAV infection can occur in all the age group of are susceptible to virus infection (Maclachlan and chickens (Snoeck et al., 2012). Usually, CIAV Dubovi, 2017). The natural outbreak of the CIA has infection does not causes clinical disease in chickens been reported from the various breeds of chicken older than 3 or 4 weeks of age, albeit it is responsible include White Leghorn cockerels, Black Australaurp, for immunosuppression and subsequently secondary Rhode Island Red and broiler breed from India (Kamdi infections. Adult birds with nutritional deficiencies or et al., 2016). Although there are no instances of clinical other immunosuppressive viral infections generally disease in other species of birds, antibodies against show marked anemia after CIAV infection (Umar et CIAV were demonstrated in Japanese quails (Farkas et al., 2014). Aflatoxins in higher doses lead to elevated al., 1998), ostriches, turkeys, ducks, and geese mortality, immunosuppression and possibly vertical (Gholami-Ahangaran et al., 2013; Shettima et al., transmission of CIAV (Kuscu and Gurel, 2008). CIAV 2017). There is no report of the disease in free-living infected birds are highly susceptible for the secondary wild birds. Immunohistochemical studies of the bone infections due to striking decrease in the generation of marrow and lymphoid tissues evidenced that erythroid antigen specific cytotoxic T cells and helper T cells and myeloid progenitor cells are highly susceptible to against other specific pathogens. At the same time, it CIAV infection (Adair, 2000). At the same time, the causes impairment in macrophage functions such as Fc- virus has demonstrated from the T lymphocyte receptor expression, phagocytosis and antimicrobial progenitor cells in the thymus indicating its activity (Tan and Tannock, 2005). Destruction and susceptibility for virus infection (McNulty, 1991). As a reduction of CD4+ cells result in an inadequate result, the virus multiplies in hemocytoblasts in the humoral immune response against specific vaccine bone marrow and precursor in the cortex of the agents and lead to vaccination failure (Schat, 2009). thymus. On the contrary, B cells precursors and B cells The CIAV has been reported to persist for 3 to 4 weeks are resistant to CIAV infection (Adair, 2000). in chickens with the intact immune system, but persistence for up to 7 weeks in immunocompromised 6. Pathogenesis chicks has been demonstrated (Eltahir et al., 2011). The In case of CIA, severity of the clinical disease, presence of maternal antibodies has been reported to generation of immunity and appearance of clinical prevent clinical disease in young chicks (Umar et al., signs is determined by the route of entry of the virus, 2014). Age resistance to clinical disease resulting from virus strain and concurrent infections of other viral or CIAV infection has been suggested to develop by 2 to 3 bacterial infections (van Santen et al., 2004). CIAV has weeks of age (Haridy et al., 2009). Hence, most a tropism for the hemocytoblasts of the bone marrow infections with CIAV have been suggested to be and lymphoblast in the thymus cortex (Fatoba and subclinical due to passive immunity and age resistance Adeleke, 2019). Pictorial presentation is depicted in Fig (Snoeck et al. , 2012). Sixteen to eighteen days 1. The virus can be located at 3-4 day post-inoculation following infection, granulopoiesis and erythropoiesis in the hemocytoblast of the bone marrow and activity is restored and the immunocompetence of the responsible for its apoptosis. The cytolytic action of the chicken returns to levels of their uninfected hatch virus results in destruction and marked reduction of mates. The appearance of CIAV-antibodies in the erythroid and myeloid cells, this lead to anemia and serum by 21 days post-inoculation coincides with the immunosuppression respectively (Smith et al., 1993; disappearance of the virus from the blood and other Adair, 2000; Eltahir et al., 2011). As hemocytoblasts lymphoid organs. Those birds which manage to survive are also the progenitor cells for thrombocytes, their the virus attach, 35 days after infection clinical, destruction causes thrombocytopenia and subsequently hematologic and pathologic parameters return to intramuscular hemorrhages observed in CIAV normal (Schat and van Santen, 2008). Older chickens infections (McNulty, 1991). Similarly, precursor T usually become resistant to virus induced anemia; also cells in the thymus cortex are involved in the early viral it won’t affect egg production significantly and do not cytolytic infection leading to the rapid depletion of show clinical signs. CIAV affected older birds remain cytotoxic and helper T cells and immunosuppression. chronically or persistently infected and transmits virus Infected precursor T cells from the thymus migrate to both horizontally and vertically. Moreover, virus can the spleen; also CIAV has been reported to infect attend latency in the gonads and it is unaffected by the mature T cells in the spleen and brings their apoptosis presence or absence of virus neutralizing antibodies (Adair, 2000). Additionally, experimental studies in a (Schat, 2009). day old chicks have demonstrated simultaneous and independent infection of the thymus and spleen by 7. Clinical Features of CIA concurrent detection of CIAV in these organs following Chicken anemia virus causes an acute, immuno-

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Fig 1: CIAV immunopathogenesis (Adair, 2000).

suppressive disease of young chickens, clinically consistent lesions (Dhama et al., 2008; Kamdi et al., characterized by , lethargy, depression, 2015). The bone marrow atrophy is also a characteristic drooling of wings, ruffled feathers, pallor of comb and finding in the CIA infected birds and is best evaluated wattle, beak and mucous membranes; cutaneous, in the femur marrow. Affected bone marrow has been subcutaneous, and intramuscular hemorrhages; reported to change from a red to pale yellow to whitish increased mortality (Ganar et al., 2017; Adedeji et al., color with fatty consistency (Orakpoghenor, 2019). 2016), growth retardation and paralysis (Engstrom and Atrophy of bursa of Fabricius (BF) with a reduction in Luthman, 1984). Classical clinical disease is noticed in its size is less commonly encountered in the CIA chickens of 2-4 weeks of age with characteristic anemia infected birds. BF outer wall becomes translucent; having lowered hematocrit (6% to 27%). The anemia is therefore inner plicae may become visible (Kamdi et a specific sign and found to be at a peak after 14 to 16 al., 2016). More pronounced atrophy BF and spleen days of infection (Smith et al. , 1993). Infected birds with enlargement and mottling of the liver have been have a mortality of 5-10%, however, the mortality rate reported due to CIAV infection, but these lesions of 60% has been reported from the CIA infected flocks largely correlate to other secondary infections (Miller (Smith et al., 1993; Shettima et al., 2017). Birds that and Schat, 2004). There has been a report of managed to survive, recover from anemia after 20-28 subcutaneous and muscular hemorrhages as well as days of infection. Chickens concomitantly infected hemorrhages in the proventricular mucosa associated with other viruses such as infectious bursal disease with severe anemia (Toro et al., 2009; Kamdi et al., virus, avian adenoviruses, reticuloendotheliosis virus, 2015). In the face of secondary bacterial infections, air avian reoviruses or marek’s disease virus showed more sacculitis, pericarditis, pneumonia, and gangrenous severe and aggravated form of the disease (Smith et al. , dermatitis may be observed (Smith et al. , 1993). 1993). CIAV infection in a chicken reported to produce Histopathologic changes were described as decreased hematocrit, leucopenia, erythropenia, and panmylopthisis and generalized lymphoid atrophy. thrombocytopenia (Kamdi et al., 2016). Decreased Hypoplasia of both erythroid and myeloid series cells clotting is most likely the consequence of in the bone marrow has been reported (Toro et al. , thrombocytopenia which is the reason for CIA 2009). There has been a report on replacement of associated hemorrhages (Markowski ‐Grimsrud and hematopoietic cells by adipose tissue or proliferating Schat, 2003). stromal cells in the early stages of the disease as described by Smyth and Schat (2013). At 20 dpi, 8. Gross and Microscopic Lesions regenerative areas of increasing number of CIA induced lesions may vary depending on its proerythroblasts and granulocyte followed by portal of entry, viral dose, age of the bird, nutritional hyperplasia of bone marrow at 20 to 24 dpi (Smyth and status, other bacterial and viral infections and immune Schat, 2013). Thymus had severe lymphoid depletion; status of the bird. Most frequently, moderate to severe cortex and medulla were atrophied with hydropic thymic atrophy, sometimes almost complete absence of degeneration of residual cells and occasional necrotic thymus lobes have been documented as one of the most foci but non-lymphoid leukocytes and stromal cells

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remain unaffected. Chicks that manage to survive, repopulation of the thymus with lymphocytes become 10. Prevention and Control distinct by 20-24 days and appear normal after 32-36 There is no specific cure for the disease and days (Schat and van Santen, 2008). Bursa had mild to virtually eradication of CIA is not possible, therefore severe lymphoid follicle atrophy with occasional small poultry producers have to rely on various control necrotic foci in folded epithelium along with hydrophic modalities. The control measures for the CIA should be epithelial degeneration, perifollicular edema and aimed to improve hygiene and poultry health; to follow proliferation of reticular cells (Kamdi et al., 2015). strict biosecurity measures and standard management Spleen had depletion of T cells with hyperplasia of practice as well as regular maternal vaccination before reticular cells in the lymphoid follicle as well as in to start laying (Oluwayelu, 2010). Attention should be Schweiger-Seidl sheath (Hussein et al ., 2012). Necrotic paid to forestall immunosuppression by environmental foci were observed in the liver, kidneys, lungs, factors, nutritional deficiencies and by other viral and proventriculus and caecal tonsils. Lymphoid follicles bacterial infections. Proper immunization and genetic had been depleted of cells and appeared swollen. The selection should be practiced to increase the resistance liver was swollen and sinusoids were dilated. so that challenges of immunosuppressive agents can be Eosinophilic intranuclear inclusion can be observed in bear up by the flock (Hoerr, 2010). The immunization bone marrow and thymus of infected birds (Goryo et of breeder flocks against CIAV has been reported to al., 1989). Occasionally, intranuclear inclusions can be ensure more protective levels of passive immunity or detected in the spleen, proventriculus, lung, kidney, the progeny chicks during the first few weeks of life bursa of Fabricius and skin (Smyth et al., 1993). (Dhama et al., 2008). Maternal anti-CIAV antibodies in chicks help to minimize vertical transmission, therefore 9. Diagnosis regular vaccination and sero-monitoring (six weeks Tentatively CIA is diagnosed on the basis of post vaccination) of breeder flocks during the rearing clinical signs, history and pathologic findings. The period is necessary to avoid vertical transmission definitive diagnosis of the CIA can be made by (Oluwayelu, 2010). The live attenuated virus vaccines isolation and identification of virus, demonstration of are available to prevent CIA and it is recommended to virus antigen in impression smears, tissue sections vaccinate the breeder flock between 9 and 15 weeks of (Dhama et al., 2008) as well as by demonstration of age (Schat and van Santen, 2008). Since, concurrent virus specific antibodies in the serum. CIAV can be infections with immunosuppresive agents such as isolated in the cell culture or in embryonated eggs but it Reticuloendotheliosis virus, Marek’s Disease virus, or is tedious, slow and expensive process. To isolate the Infectious Bursal disease virus causes a delay in the virus, chloroform treated tissue extracts from the development of age resistance and increased suspected birds are inoculated in the MDCC-147 and pathogenicity of CIAV, immunosuppressive disease MDCC-MSB1 or into immunocompromised (CIAV- control has been suggested to be integrated into the antigen and anti-CIAV antibody negative) day old CIAV control program. Therefore, the introduction of chicks. MDCC-147 and MDCC-MSB1 are the the CIAV vaccination program requires consideration lymphoblastoid cell line derived from the Marek’s to the nature and immunopathogenesis of CIAV disease tumor (Krapez et al., 2006; Schat and van infection in relation to other agents (Oluwayelu, 2010). Santen, 2008). Viral DNA base detection methods like polymerase chain reaction (PCR), quantitative PCR, in- 11. Conclusion situ hybridization, etc can be used. Routinely, PCR CIA is an important immunosuppressive disease assays and q-PCR have been frequently employed for in poultry and responsible for the heavy economic the detection of CIAV DNA in infected cell culture, losses throughout the world. Typically it is chicken tissues, vaccines, excretions/secretions from characterized by immunosuppression, aplastic anemia chicken and archived formalin-fixed tissues. PCR assay and atrophy of thymus, bone marrow and other is a most frequently used laboratory technique to detect lymphoid organs. There is no specific treatment for the the CIAV DNA from the tissue of affected birds and it diseases and practically eradication is also not possible. is specific and more sensitive as compared to cell Therefore, it is a need to conduct region wise molecular culture virus isolation and other methods (Miller et al., epidemiological studies so as to know exact strain and 2005). Droplet digital Polymerase Chain Reaction type of the virus circulating in the area. Accordingly, to (ddPCR) assay found to be more sensitive and accurate control the disease strict biosecurity measures and to detect CIAV contamination of vaccines (Li et al ., breeder vaccination programmes can be implemented. 2019). Alternatively, virus antigen in various tissues Also, there is growing need to develop ways to reduce can be detected by immunohistochemistry or losses due to subclinical infections. Detection of CIAV immunofluorescence technique. The presence of CIAV from the diseased and healthy individuals suggests specific serum antibodies can be confirmed by virus further studies to explore exact zoonotic potential of the neutralization test (VNT) (Oluwayelu, 2010) and CIAV. ELISA (Shettima et al., 2017).

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Journal of Poultry Science and Technology | January-March, 2020 | Volume 08 | Issue 01 | Pages 16-22 © 2020 Jakraya 22