About FOR 5130
The chicken has a long history as a biomedical animal model and substantially contributed to the knowledge in many research areas including cancer biology, microbiology, virology and immunology1. In addition, the chicken embryo became a leading model organism in developmental biology due to its accessibility2. Beyond their critical role in research, chickens are one of the most important sources of animal protein worldwide. A plethora of pathogens infect
chickens, threatening animal health and welfare, food safety and the livelihood of farmers worldwide, and pose a risk of zoonotic infections3. Therefore, domestic chickens are the most vaccinated species in industrialized countries to protect them from these pathogens. To reduce animal losses, antibiotics are still frequently used to fight bacterial infections; however, this contributes to the alarming rise of antibiotic resistances that threaten food safety and public health4. Therefore, a broader understanding of the chicken immune system and vaccine responses are required to provide a better protection against dangerous pathogens in the future. Infectious bursal disease virus (IBDV) is one of the most important immunosuppressive pathogens for chickens worldwide5, 6. Despite the availability of many licensed commercial vaccines, field outbreaks occur due to insufficient vaccine protection7. Live-attenuated vaccines are frequently used but can have residual immunosuppressive effects on immunized birds. Humoral immunity was shown to be important for protection against IBDV, as maternal antibodies may reduce or prevent disease. Beyond that, cell-mediated immune responses are thought to play a role in controlling virus replication8, 9. However, the role of cellular immune responses, the genotype and age of chickens in IBDV pathogenesis remains poorly understood.
Highly pathogenic (HP) avian influenza viruses (AIVs) threaten poultry industries and are decimating wild birds (especially aquatic birds), poultry and mammals worldwide. In chickens, HPAIV leads to severe outbreaks with mortality rates of up to 100%, resulting in the suffering of the animals and devastating economic losses10. The virus not only infects the respiratory tract but also spreads systemically and can also infect humans11. Subtype-specific vaccines have been used in Asia and Africa to mitigate the economic losses of AIVs in poultry and to reduce the zoonotic risk. Recently, vaccination has been encouraged in Europe and the Americas to mitigate the socioeconomic impact of the virus12. There are important gaps in our knowledge of the immune response to the different AIV pathotypes and vaccines. Therefore, we will combine the expertise of the ImmunoChick (FOR5130) teams to improve our understanding of the immune response to AIV pathotypes and vaccines.
Another important pathogen in chickens is the highly oncogenic Marek’s disease virus (MDV), also known as gallid herpesvirus type 2 (GaHV-2). It causes high economic losses of approximately 1 billion € in the poultry industry annually worldwide13. MDV causes a variety of clinical symptoms including neurological disorders and immunosuppression, making the animals more susceptible to secondary infections. Most importantly, the virus efficiently induces malignant T cell lymphomas, which are considered to be the most prevalent cancer in animals14. Over the years, MDV continuously evolved towards a greater virulence, resulting in virus strains that can overcome the protection of various vaccines and cause a mortality of up to 100%. Therefore, we need a better understanding of immune responses against MDV to develop more potent vaccines and protect our chicken flocks against this deadly pathogen.
Aside from viruses, bacterial infections play a very important role in the poultry industry. Bacteria of the genus Salmonella are able to cause acute and chronic diseases in poultry. Moreover, Salmonella-contaminated chicken eggs and meat products are the most common sources of human salmonellosis. To prevent colonization of chickens with the serovars Salmonella Enteritidis and Typhimurium in layer flocks, vaccination programs have been implemented for many years with varying success15. Very young chicks are especially susceptible to Salmonella infections and show significant morbidity and mortality. The susceptibility decreases over time as adult chickens are colonized and systemically infected in the absence of clinical signs. Importantly, humoral responses are not sufficient to clear primary Salmonella infections16-18. Therefore, it is crucial to investigate the role of αβ and γδ T cells in the immune response upon infection and vaccination19.
The adaptive immune system, with its B and T cell subsets, plays a crucial role in the defense against important pathogens including IBDV, AIV, MDV, and Salmonella spp. B cells produce antibodies that neutralize pathogens and prevent their spread. In contrast, T cells (including αβ and γδ subtypes) orchestrate immune responses, directly killing infected cells or supporting other immune functions. Notably, γδ T cells are highly abundant in blood, in contrast to humans and mice20, suggesting they may play a specialized role in avian immunity. Knowledge of the distinct roles of these lymphocytes is crucial for pathogens like MDV and Salmonella spp., where humoral responses alone are not sufficient to provide protection. This highlights the importance of understanding how T cells, especially αβ and γδ subsets, contribute to pathogen clearance and enhance vaccine-mediated protection.
While significant progress has been made in understanding the chicken immune system and its responses to various pathogens, critical knowledge gaps remain, particularly in the context of adaptive immunity and its interaction with both viral and bacterial pathogens. Knockout chickens have emerged as a powerful tool to elucidate these gaps by dissecting the roles of specific immune cells and components. For example, the contribution of αβ and γδ T cells to vaccine responses and pathogen defense remains only partially understood despite their critical importance in shaping adaptive immunity. Moreover, the molecular ligands of γδ T cells, such as CD1, butyrophilin, and BG molecules, and their roles in immune modulation and maintaining barrier integrity remain elusive. While B cells are known to be essential for humoral immunity21, their interactions with T follicular helper cells in germinal centers, the processes of affinity maturation, and the specific immune mechanisms underlying vaccine protection require further
investigation. These gaps are particularly evident in the immune responses to important pathogens such as IBDV, AIV, MDV, and Salmonella spp., where current vaccines often provide suboptimal protection or fail to prevent outbreaks. In addition, the influence of type I and III interferons on adaptive immunity, viral replication, and vaccine efficacy remains poorly characterized. We will address these knowledge gaps using innovative tools developed in the first ImmunoChick funding period, such as TCR sequencing, pathogen-specific MHC peptides, MHC tetramers, and genetically modified chickens. Combined with the complementary expertise and synergistic teamwork of the ImmunoChick Research Unit
(FOR5130), these approaches offer a unique opportunity to advance our understanding of the avian immune system and lay the groundwork for innovative intervention strategies.