Role of AKT1 & SIVA1 in resistance to avian salmonellosis

家禽是人类沙门氏菌感染的主要宿主，因为某些菌株能够在禽类肠道和生殖道中定植。鸟类通常在没有明显症状的情况下携带这种细菌；然而，某些类型的沙门氏菌在家禽中引起严重的类似伤寒的疾病，造成巨大的福利和经济成本。全球人口增长和日益富裕正在推动对禽肉和禽蛋的需求，需要加强这类产品的供应和安全。虽然疫苗在一些国家是分层使用的，但全世界每年饲养的550亿只鸡中的大多数都缺乏对沙门氏菌感染的保护。我们和其他人已经发现，一些鸡对沙门氏菌的抵抗力表现出遗传差异。有选择地培育对沙门氏菌感染有更好抵抗力的鸟类可能是可行的；然而，这需要确定与抗性相关的因素并了解它们如何起作用。通过分析耐药性不同的鸟类的遗传物质，我们在实验室研究和商业家禽种群中都找到了鸡染色体上保护人们免受伤寒沙门氏菌病的一个区域。最近的研究现在已经解决了与少数基因抗性相关的区域。影响该区域两个基因（AKT1和SIVA1）的变异解释了为什么鸟类对沙门氏菌有不同的反应，这是非常可信的，因为编码的蛋白质控制着影响细菌命运的宿主过程。例如，AKT1和SIVA1控制感染细胞的死亡和免疫反应的诱导，但具有相反的活性。我们不可能预测影响这些基因的遗传变化将如何改变它们的表达或活性。此外，目前还不清楚这些因素如何控制沙门氏菌在鸟类中的生长和传播。因此，我们建议：检查禽类是否通过激活AKT1和SIVA1的表达或功能对沙门氏菌感染作出正常反应。我们将在培养的鸡细胞和完整的鸟类细胞中检验这一点，并将任何差异与宿主反应和细菌的命运联系起来。检查已知对沙门氏菌感染的抗性不同的鸡系是否在AKT1和SIVA1的水平或激活上有所不同。3. 使用特定的抑制剂和细菌菌株来确定AKT1的激活对于沙门氏菌在鸟类中生长和传播是必要的。确定商品家禽种群中影响AKT1和SIVA1基因变化的性质、频率和后果。这将有助于鸡的选择性繁殖，显示出更好的抵御沙门氏菌感染的能力。我们很幸运地得到了世界上最大的家禽养殖公司之一（Erich Wesjohann Group）的支持，他们将提供鸟类、基因组序列、专业知识和项目总成本的10%。这反映了拟议研究对行业的价值。该联盟进行了富有成效的合作，提出的研究是我们最近联合研究的及时、合理和可行的延伸。

Poultry are a key reservoir of human Salmonella infections owing to the ability of some strains to colonise the avian intestines and reproductive tract. Birds often carry the bacteria in the absence of overt symptoms; however some types of Salmonella cause severe typhoid-like diseases in poultry that exert substantial welfare and economic costs. Global population growth and rising affluence are fuelling demand for poultry meat and eggs, and a need exists to enhance the supply and safety of such. Though vaccines are used in layers in some countries, most of the 55 billion chickens reared annually worldwide lack protection against Salmonella infection. We and others have discovered that some chickens exhibit heritable differences in resistance to Salmonella. It may be feasible to selectively breed for birds with improved resilience to Salmonella infection; however this requires the identification of resistance-associated factors and knowledge of how they act. By analysing the genetic material of birds that differ in resistance, we have located a region of the chicken chromosome that confers protection against typhoidal salmonellosis, both in laboratory studies and commercial poultry populations. Recent studies have now resolved the region associated with resistance to just a handful of genes. It is highly plausible that variation affecting two genes in this region (AKT1 and SIVA1) explains why birds react to Salmonella in different ways, as the encoded proteins control host processes that impact on the fate of bacteria. For example, AKT1 and SIVA1 control the death of infected cells and the induction of immune responses, but have opposing activities. It is not possible for us to predict how the genetic changes affecting these genes will alter their expression or activity. Moreover, it is unclear how such factors may control the growth and spread of Salmonella in birds. We therefore propose to:1. Examine if birds normally respond to Salmonella infection by activating the expression or function of AKT1 and SIVA1. We will examine this in cells cultured from chickens, as well as in intact birds, and associate any differences with host responses and the fate of the bacteria.2. Examine if lines of chicken known to differ in resistance to Salmonella infection vary in the levels or activation of AKT1 and SIVA1. 3. Use specific inhibitors and bacterial strains to establish that AKT1 activation is necessary for Salmonella to grow and spread in birds.4. Define the nature, frequency and consequences of genetic changes affecting AKT1 and SIVA1 in commercial poultry populations. This will aid the selective breeding of chickens that show improved resilience to Salmonella infection.We are fortunate to have the support of one of the world's largest poultry breeding companies (Erich Wesjohann Group), who will provide birds, genome sequences, expertise and 10% of total project costs. This reflects the value of the proposed studies to the industry. The consortium has productively collaborated and the proposed studies are a timely, logical and feasible extension of our recent joint research.