Introduction

Hantaviruses are a group of zoonotic viruses, meaning they can be transmitted between animals and humans. Hantavirus infection causes two severe diseases in humans: haemorrhagic fever with renal syndrome (HFRS) in Eurasia and hantavirus cardiopulmonary syndrome (HCPS), also called hantavirus pulmonary syndrome in the Americas. While HFRS and HCPS are distinct diseases, there is significant overlap of symptoms, clinical signs and pathogenic changes.¹

Autoimmune disorders are a broad range of conditions characterised by your own immune system attacking your body. With an autoimmune disorder, your immune system attacks and damages your body cells, which normally should only attack foreign invaders, such as viruses and bacteria, and not respond to self-cells. Common findings in autoimmune diseases are immune cells (T and B cells) that are reactive to normal self constituents; these immune cells are called ‘autoreactive’.

In autoimmune disorders, we commonly see the production of autoantibodies, which are key markers of autoimmunity and are useful for diagnosis. Autoimmune conditions can affect any organ and individuals of any age, though there is a greater prevalence of autoimmune conditions in women than men.² Common examples of autoimmune disorders include: lupus, rheumatoid arthritis and multiple sclerosis.

This article explores how hantavirus infections may be linked to autoimmune disorders.

Overview of Hantavirus infection

Hantaviruses have an almost global distribution, with species present throughout Eurasia, the Americas and Africa. However, evidence of human infection linked to African species is limited.

Transmission

Rodents are the main natural hosts or carriers of HFRS and HCPS, causing hantaviruses. Rodents are suitable carriers of these viruses, as they are persistently infected but are not negatively impacted by the virus itself.

Other possible hantavirus carriers include bats, moles, shrews, reptiles and fish. Humans are exposed to and infected with hantaviruses by inhaling viruses from rodent saliva, urine and faeces or, rarely, via rodent bites.¹

Pathogenesis

The endothelial cells of capillaries, the lining cells of the smallest type of blood vessel, are the main targets of hantavirus infection. Increased permeability of blood vessels is key to disease pathogenesis (development of disease). This increase in permeability is linked to changes in the endothelial cell membrane that may arise due to: virus binding to cell receptors, immune responses and inflammatory responses.

In HFRS, activation of endothelial cells leads to platelet activation and altered blood clotting. HFRS, causing hantaviruses mainly infect the capillaries in the kidneys. Whereas with HCPS, causing hantaviruses, the capillaries of the lungs are primarily targeted. Unfortunately, the infection level and clinical presentations are often difficult to assess.¹

Clinical presentation, symptoms and outcomes

While HCPS and HFRS are different syndromes, they share several common features. Both syndromes induce a strong inflammatory response, affect vascular endothelial cells, and behave like a systemic disease. Both can result in kidneyfailure and respiratory problems, such as hypoxia. 

Typical features of HFRS are increased vascular permeability, dysregulated blood clotting, and acute (short-term) kidney injury. The infection course varies depending on the individual infected and the hantavirus type. Common initial features include a high fever, headaches, nausea, abdominal and back pain and low blood pressure.

In HCPS, initial findings include headaches, chills, abdominal pain, vomiting, diarrhoea and pain behind the eyes. Some patients may experience cardiopulmonary symptoms such as a cough, tachycardia (fast heartbeat) and hypotension (low blood pressure).¹ 

Understanding autoimmune disorders

Autoimmunity occurs when the immune system attacks the body’s own tissues. Normally, the immune system only attacks foreign invaders in the body, such as viruses, bacteria and parasites.

Triggers of autoimmunity

Genetic predisposition

Current models of autoimmunity suggest autoimmune disorders arise in genetically predisposed individuals following an environmental trigger. Evidence suggests your genes (what's in your DNA, inherited from your parents) are important for developing autoimmune conditions, suggesting a heritable component. 

Observed studies of autoimmune disorders in families highlight that it is not a specific disease which is passed on, but a tendency to develop autoimmune conditions; for example, one family member may have multiple sclerosis while another may have rheumatoid arthritis. Variations in MHC genes are linked to a predisposition to developing autoimmune disorders. Other possible genes linked to autoimmunity include: IL-23R, IL-7R and NOD2.³

Environmental factors

Genes alone are not sufficient to trigger an autoimmune condition; it is suggested that a close interplay between environmental triggers and genetics is responsible for causingautoimmunity to develop. Environmental factors linked to the development of autoimmunity include smoking, Vitamin D, toxins, diet, infections, antibiotics, and dysbiosis (disruption of the balance of microorganisms in your body).³

Infection as a trigger for autoimmunity

Among all environmental triggers, infection is the most likely direct trigger of autoimmunity. Infection can trigger autoimmunity through at least two different mechanisms. The first is molecular mimicry, where there is structural similarity between self and foreign molecules. In this case, antibodies created to bind to foreign molecules may accidentally bind to the body’s own molecules due to a similar structure. 

An instance, antibodies produced against Epstein-Barr Virus (EBV) proteins. These antibodies canbind to (self) RNA-binding proteins (RBPs). Established anti-RBP antibodies can promote disease by stimulating immune responses.² Other viruses like EBV that are linked to autoimmunity include lupus, Hepatitis C, and autoimmune hepatitis. 

The second mechanism by which infection can trigger autoimmunity is when the infection stimulates the immune system in a non-specific manner.²

Investigating the link: hantavirus and autoimmune disorders

Evidence from case reports and studies 

A case study has documented a patient with autoimmune polyendocrinopathy (dysfunction of multiple hormone glands due to an autoimmune reaction) and hypophysitis (inflammatory condition of the pituitary) after Puumala hantavirus infection. Puumala hantavirus leads to nephropathia epidemica (NE), a mild form of HFRS. In this case, NE-associated autoimmune polyendocrinopathy and hypopituitarism arose likely due to autoimmune hypophysitis. The patient later developed hypothyroidism, hypogonadism and diabetes insipidus.

It is known that hormone deficiencies occur at a higher incidence in individuals who have experienced HFRS than in the general population, but the cause of these late-onset hormone defects is unknown. This case suggested that late-onset hormonal defects after hantavirus infection may develop through an autoimmune mechanism. However, it was concluded that more research was required to confirm this hypothesis.⁴

While viral infections have been linked to the development of autoimmune diseases, the link between hantavirus HFRS and chronic hormone deficiencies remains unclear. It is proposed that hantavirus infections may affect the pituitary and peripheral hormone glands, affecting the immune system andleading to the production of autoantibodies against the hormone glands. Subsequent autoimmune inflammation may explain the deficiencies of the peripheral hormonal glands, which appear more frequently after NE.⁴

Evidence suggests hypophysitis may develop by an autoimmune mechanism, and lymphocytic hypophysitis is frequently associated with autoimmune diseases. The patient in the case study showed evidence of hypophysitis.⁴ This study, therefore, highlights some evidence of autoimmunity stemming from hantavirus infection, but more research is required to prove causality.

To answer whether hantavirus could trigger an autoimmune disease, the virus must be able to replicate the mechanisms by which other infections trigger autoimmunity. Evidence that hantavirus infection can lead to the production of autoantibodies has been found, as anti-endothelial cell antibodies have been identified in NE. A case of autoimmune polyendocrinopathy and hypophysitis after Puumala hantavirus infection has been identified. 

Interestingly, hantavirus infection may boost EBV-specific memory T-cells and may reactivate EBV. This may explain some features of hantavirus infection, including increased lymphoma risk. There is strong evidence linking EBV infection with autoimmunity, so viral reactivation/ production of EBV-specific memory cells may contribute to an increased risk of autoimmunity.⁵ As with other infections, hantavirus infections can trigger nonspecific stimulation of the immune system, which is another mechanism which may lead to autoimmunity.

Challenges and limitations

A limitation og linking hantavirus infection to the development of autoimmune conditions is the lack of extensive research. There has been difficulty establishing causality and determining whether the cases of autoimmunity following hantavirus infection were coincidental or due to the virus.

Future directions

Future research seeking to establish the link between hantavirus infection and autoimmunity will need to look at the post-infection effects, observe the autoimmune phenomena in individuals following hantavirus infection, and further our understanding of how viral infections can trigger autoimmunity.

Summary

In summary, it is still unknown if hantavirus infection can directly trigger autoimmune disorders, though there is evidence that supports the hypothesis. Notably, it is already known that viral infection can lead to autoimmunity via the molecular mimicry mechanisms and nonspecific immune system stimulation. Research suggests that autoantibodies are present following hantavirus infection, but whether these increase autoimmune risk is not yet known, despite autoantibodies being a key hallmark of autoimmunity.

Furthermore, a documented case of autoimmune polyendocrinopathy and hypophysitis after hantavirus infection has been identified, and higher incidences of similar hormone dysregulation among other hantavirus survivors all provide evidence of a possible link between hantavirus infection and autoimmunity. Hantavirus infection may also lead to reactivation of EBV-specific memory cells and potentially EBV infection, which is a well-documented trigger of autoimmunity. Together, this evidence suggests hantavirus may trigger autoimmunity via nonspecific immune system stimulation and possible reactivation of EBV. However, further research is needed to determine if hantavirus is causative of autoimmune disorders.