Abstract

The principle forms of invasive Salmonella infections, typhoid fever and invasive nontyphoidal Salmonella disease (iNTS), are both characterized by intracellular growth and extracellular systemic spread of bacteria belonging to different serovars of Salmonella enterica.

Animal models have provided many insights into those host-pathogen relationships that control invasive Salmonella infections. Immunological or genetic manipulations of B- and T-cell mediated immunity, signaling pathways, cytokine networks and phagocyte effector functions modulate host resistance/susceptibility and have provided solid information on which immunological effectors control and eliminate the disease. These models have also enabled us to test different classes of vaccines and determine which ones are likely to induce the highest level of protection in other animal species and in humans.

The higher incidence of invasive Salmonella disease in patients with genetic immunodeficiencies, individuals carrying specific immune gene alleles and patients with comorbidities (e.g. malaria, severe anaemia, HIV ), indicates common resistance/susceptibility traits between mice and humans. iNTS and typhoid fever are often inferred to be immunologically similar. It would therefore be reasonable to assume that the determinants of resistance/susceptibility to these diseases are similar and require invocation of humoral and cellular immunity. However, evidence from host susceptibility and risk factor associations provides a far more complex scenario.

The presence of comorbidities in endemic area poses serious challenges to disease prevention by undermining those element of the innate immune response that are the foundations upon which vaccines build resistance. There are currently large gaps in our knowledge of the mechanisms that control Salmonella infections is humans and we still do not fully understand of how comorbidities, alone or in combination, impair immunity.

A major challenge ahead is to link risk factors/comorbidities with specific immunological/functional defects that determine increased susceptibility to infections in endemic areas. This will provide a rational pathway to develop approaches and tools to restore such defects in individuals with high risk of contracting disease.