We are living in a world with an increasingly aged population. Life expectancy in the UK now tops 80 years old, a sharp contrast to a life expectancy of 52 a mere hundred years ago. People are living longer, but at what cost?
The biggest killers worldwide are chronic diseases, namely cardiovascular disease, cancer, dementia, respiratory disease and liver disease, and ageing represents the largest risk factor. There is another worrying trend – chronic diseases are affecting more people below the age of 60 than ever before. We are living longer but the burden of chronic disease has escalated.
Infectious disease-related deaths, particularly in children below 5 years of age, have declined significantly in recent years. Even in less-developed nations the incidence of deaths from infectious diseases has fallen. Pathogens have not been absolved of all accountability however. Mounting evidence now points to a strong association between infectious diseases and several important chronic diseases.
The virus factor
Human immunodeficiency virus (HIV), which causes acquired immune deficiency syndrome (AIDS), is considered the archetypal virus that causes chronic disease. HIV primarily targets CD4+ T helper cells, slowly killing them and exhausting the immune system so that patients become highly susceptible to opportunistic infections, such as Pneumocystis carinii, and certain cancers, including Kaposi’s sarcoma. However, the link between virus infection and cancer was established well before the HIV epidemic.
In 1911 Peyton Rous was the first person to discover that a malignant tumour was caused by a microscopic infectious agent much smaller than a cell or bacterium. The infectious agent became known as Rous Sarcoma Virus (RSV). Not only did viruses cause cancer, they were transmissible.
Research on oncoviruses paved the way for the discovery of oncogenes – those genes that when activated out of context can drive cell transformation. RSV is a type of retrovirus, a group of viruses that can insert their genes into our DNA. Whenever an infected cell replicates, new viral genes are transcribed and the retrovirus spreads. On occasion retroviral genes insert themselves next to oncogenes, causing oncogene expression and tumour progression.
Many more oncoviruses have since been discovered, including the retroviruses feline leukaemia virus, mammary tumour virus and human T-lymphotrophic virus. In 1964 Epstein-Barr virus (EBV) was the first virus confirmed to cause a human malignancy. However, EBV is not a retrovirus but a member of the herpesvirus family and is better known as the causative agent of glandular fever (mononucleosis). Importantly, it is also associated with B cell lymphomas (e.g. Hodgkin’s lymphoma and Burkitt’s lymphoma), as well as the autoimmune diseases rheumatoid arthritis and systemic lupus erythematosus (SLE).Remarkably, the underlying cause of Kaposi’s sarcoma was also found to be a human herpesvirus (Kaposi’s sarcoma-associated virus). In immunocompromised patients Kaposi’s sarcoma-associated virus is left unchecked and allowed to infect multiple skin cells, ultimately initiating malignant transformation. This interplay demonstrates the relationship between infectious pathogens, the immune system and chronic disease.
Most of these oncoviruses are transmissible, meaning there is the possibility of developing vaccines to treat certain cancers.
The diversity of microbiota, and differences in prevalent microbial species, have both been associated with chronic disease phenotypes.
Human papilloma virus (HPV) is the causative agent of several cervical and oral cancers. In the UK around 3,000 women are diagnosed with cervical cancer each year. HPV transforms epithelial cells that line the mucous membrane of the cervix, instructing those cells to divide uncontrollably. Instead of inserting retroviral genes next to oncogenes, viruses like HPV and EBV induce transformation by subverting cellular signalling processes.
As many as 30 types of HPV can be transmitted sexually, of which HPV types 6 and 11 cause genital warts, while HPV types 16 and 18 can initiate invasive cancerous lesions. Fortunately, a vaccine is available that targets all four types of HPV, and it has been estimated the vaccine will reduce the incidence of the most common form of cervical cancer by 70%. This approach clearly illustrates how the immune system can be exploited in order to prevent cancers by targeting the viruses that induce them.
It has been estimated that one-third of the world’s population has been infected with hepatitis B virus (HBV) and that 350 million are chronically infected. Another 200 million people are chronically infected with the related hepatitis C virus (HCV).
Persistent infection with both HBV and HCV can result in chronic liver disease, known as viral hepatitis, and in some cases can progress to cancer. HBV and HCV are known as ‘slow viruses’ as people may succumb to cancer 15–20 years after initial viral exposure.
HBV is actually a vaccine-preventable disease but there is no vaccine available for HCV. Therefore, the only option for many people with chronic HCV infection is IFN- α and anti-viral therapy, and if that fails transplantation. The direct impact that HBV and HCV have on chronic disease means they remain significant economic and health burdens worldwide. Viruses are not the only pathogens associated with chronic disease. The discovery that the bacterium Helicobacter pylori was the major cause of chronic gastritis and gastric ulcers helped establish the connection between infectious disease and chronic disease. H.pylori is actually part of the natural gastric microbiota and only becomes pathogenic following colonisation with virulent strains.
Another bacterium, Chlamydia pneumoniae, has been linked to cardiovascular disease. Other factors, such as obesity and diabetes are the main risk factors, but C. pneumoniae infection has been linked to an increased susceptibility to cardiovascular disease. The establishment of chronic inflammation or direct infection of cardiomyocytes are the likely causes.
Our microbiota, the vast array of symbiotic bacteria, archaea, viruses and fungi that live on or inside us, may also hold the key to understanding the prevalence of chronic disease. Perturbations in the normal, healthy microbiota, known as microbial dysbiosis, have been linked to a range of chronic diseases, such as inflammatory bowel disease, rheumatoid arthritis, type 1 diabetes, cancer, asthma and even cognitive decline. The diversity of microbiota, and differences in prevalent microbial species, have both been associated with chronic disease phenotypes.
The microbiota may also be necessary for the correct development of the immune system. Microbial dysbiosis has been associated with heightened inflammation, the development of pathogenic Th17 responses and the breakdown of immunological tolerance. This may make certain individuals more susceptible to a range of chronic diseases.
The gut microbiota also changes in the elderly, although how this impacts chronic disease susceptibility remains unknown. The difficulty has been proving causality between certain microbiota species and the development of chronic disease, although new advances in molecular technologies will no doubt enhance the discovery process.
Exacerbations and ageing
Acute and transient infectious episodes have also been linked to chronic disease. For example, acute respiratory infections are associated with disease exacerbations in asthma and chronic obstructive pulmonary disease (COPD) patients. The main culprits are influenza viruses and rhinoviruses, which cause immune cells to release pro-inflammatory cytokines. Viral exacerbations can trigger severe asthma attacks and acute episodes of COPD, both of which can be life-threatening. In addition, viral exacerbations can contribute to the accelerated decline in respiratory function.
Episodes of acute infection also become more frequent as we age. The elderly are more susceptible to infectious diseases and respond poorly to vaccination, due largely to a decline in immune function, known as immunosenescence. In addition, the elderly experience an underlying state of chronic inflammation, known as inflammaging, which may be related to a heightened susceptibility to chronic disease.
Infections are thought to influence chronic disease in several ways, including direct and indirect cell transformation, chronic inflammation, permanent tissue damage and heightened predisposition to pathologies.
This fascinating area of research will be the focus of an upcoming meeting hosted by the BSI Infection and Immunity Affinity Group and London Immunology Group at the Royal College of Anaesthetists on 12 July 2018. The meeting aims to highlight cutting-edge research on infection and chronic disease from key researchers across the UK.
Centre for Inflammation and Tissue Repair, UCL Respiratory, University College London