Acute senescence: a novel host defence counteracting typhoidal Salmonella
Lead Research Organisation:
University of Sheffield
Department Name: School of Biosciences
Abstract
Typhoid fever is an infectious disease caused by Salmonella Typhi resulting in 14 million cases, 140,000 deaths and 8 million daily-adjusted life years lost to ill health per annum. The problem is exacerbated by antimicrobial-resistance and poor diagnostics due to a lack of suitable biomarkers. We must advance understanding of typhoid to accelerate development of therapeutic interventions, which represent priorities for the WHO and UN Sustainable Development Goals.
S.Typhi lives inside our gut cells before infecting the bloodstream (bacteraemia) and spreading to different organs in the body resulting in typhoid fever. My UKRI FLF was awarded upon our discovery that S.Typhi causes premature ageing in human cells by releasing a toxin. The typhoid toxin causes DNA damage in our cells, in much the same way as UV light, and this elicits an ageing-like process in cells called acute senescence. Ageing comes with increased susceptibility to infection. Thus, we initially hypothesised that the toxin causes senescence to make human cells more vulnerable to infection. To our surprise, discoveries during my FLF indicate the opposite may be true and that acute senescence is a novel immune defence pathway, which can attack S.Typhi through antimicrobial activities and help prevent typhoid. This is unexpected yet, in early life, acute senescence is known to prevent cancer, thus, we hypothesise that acute senescence may have co-evolved to counteract infectious diseases such as typhoid. The FLF renewal aims to lead a new area of research investigating Acute Senescence Antimicrobial Responses (ASAR).
Our experiments with cultured cells and clinical samples indicate that when typhoid toxin causes DNA damage, cells signal their distress by
(i) entering into a senescent state through the human gene p21, and by
(ii) secreting antimicrobial proteins into the extracellular environment.
In cancerous cells, p21 stops the cells from growing into tumours and secrete proteins that attracts immune cells to destroy the cancer cells. Thus, we will determine whether p21 launches ASAR: (i) by suppressing the growth of S.Typhi living inside senescent cells, and (ii) by suppressing the growth of extracellular S.Typhi via secretion of antimicrobials and immune cell attractants.
This is how we will investigate ASAR:
Objective 1: Advance discovery of antimicrobials secreted in human participants with typhoid.
A clinical study revealed that the duration of bacteraemia in human participants with typhoid was shorter with wild-type (WT) S.Typhi carrying typhoid toxin than toxin-negative (TN) S.Typhi (WT 48 hours; TN 96 hours). This indicates that unknown factors are attacking WT but not TN S.Typhi. Thus, we will determine whether clinical samples from participants infected with WT contain antimicrobial biomarkers released in response to typhoid toxin.
Objective 2: Determine whether antimicrobial responses are regulated by senescence.
We will validate whether antimicrobial biomarkers identified through objective 1 rely upon p21-mediated senescence. This will be achieved by examining Salmonella-infected cells undergoing senescence in human tissue culture experiments and infected mice
Objective 3: Establish antimicrobial activities of the Acute Senescence Antimicrobial Response
We will progress from objective 2 by elucidating whether secreted senescent-associated antimicrobial biomarkers attack extracellular S.Typhi and whether p21 in the infected senescent cells suppress infection by activating intracellular defences against S.Typhi.
By revealing ASAR as a novel innate defence suppressing Salmonella infection, my team will discover a new immune pathway that combats typhoid fever, which will be significant during infections by related pathogens of global importance. By leading a new area of research on ASAR, the renewal will facilitate ways to enhance ASAR and discover of translatable antimicrobial biomarkers with diagnostic potential.
S.Typhi lives inside our gut cells before infecting the bloodstream (bacteraemia) and spreading to different organs in the body resulting in typhoid fever. My UKRI FLF was awarded upon our discovery that S.Typhi causes premature ageing in human cells by releasing a toxin. The typhoid toxin causes DNA damage in our cells, in much the same way as UV light, and this elicits an ageing-like process in cells called acute senescence. Ageing comes with increased susceptibility to infection. Thus, we initially hypothesised that the toxin causes senescence to make human cells more vulnerable to infection. To our surprise, discoveries during my FLF indicate the opposite may be true and that acute senescence is a novel immune defence pathway, which can attack S.Typhi through antimicrobial activities and help prevent typhoid. This is unexpected yet, in early life, acute senescence is known to prevent cancer, thus, we hypothesise that acute senescence may have co-evolved to counteract infectious diseases such as typhoid. The FLF renewal aims to lead a new area of research investigating Acute Senescence Antimicrobial Responses (ASAR).
Our experiments with cultured cells and clinical samples indicate that when typhoid toxin causes DNA damage, cells signal their distress by
(i) entering into a senescent state through the human gene p21, and by
(ii) secreting antimicrobial proteins into the extracellular environment.
In cancerous cells, p21 stops the cells from growing into tumours and secrete proteins that attracts immune cells to destroy the cancer cells. Thus, we will determine whether p21 launches ASAR: (i) by suppressing the growth of S.Typhi living inside senescent cells, and (ii) by suppressing the growth of extracellular S.Typhi via secretion of antimicrobials and immune cell attractants.
This is how we will investigate ASAR:
Objective 1: Advance discovery of antimicrobials secreted in human participants with typhoid.
A clinical study revealed that the duration of bacteraemia in human participants with typhoid was shorter with wild-type (WT) S.Typhi carrying typhoid toxin than toxin-negative (TN) S.Typhi (WT 48 hours; TN 96 hours). This indicates that unknown factors are attacking WT but not TN S.Typhi. Thus, we will determine whether clinical samples from participants infected with WT contain antimicrobial biomarkers released in response to typhoid toxin.
Objective 2: Determine whether antimicrobial responses are regulated by senescence.
We will validate whether antimicrobial biomarkers identified through objective 1 rely upon p21-mediated senescence. This will be achieved by examining Salmonella-infected cells undergoing senescence in human tissue culture experiments and infected mice
Objective 3: Establish antimicrobial activities of the Acute Senescence Antimicrobial Response
We will progress from objective 2 by elucidating whether secreted senescent-associated antimicrobial biomarkers attack extracellular S.Typhi and whether p21 in the infected senescent cells suppress infection by activating intracellular defences against S.Typhi.
By revealing ASAR as a novel innate defence suppressing Salmonella infection, my team will discover a new immune pathway that combats typhoid fever, which will be significant during infections by related pathogens of global importance. By leading a new area of research on ASAR, the renewal will facilitate ways to enhance ASAR and discover of translatable antimicrobial biomarkers with diagnostic potential.
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ORCID iD |
| Daniel Humphreys (Principal Investigator / Fellow) |