What Is The Role Of The Immune System In Combating Parainfluenza Infection?

Introduction 

Parainfluenza infection, often confused with Influenza or the common cold due to the similarities in its symptoms, is caused by the human parainfluenza virus (HPIV). You might have been affected by HPIV infection without even realising it, as the symptoms can be mild in most people, but it can also lead to severe consequences in high-risk patients, such as younger children, elderly and immunocompromised patients. 

It is a very common disease that typically affects younger children and infants. It is reported that >75% of children above the age of 5 and approximately 90% of adults have a previous infection of HPIV. You generally develop milder symptoms as you age and after the first infection. This is a result of the successful elimination of the disease by the immune system in the past. In this article, we will delve deeper into the roles of the innate and adaptive immune system in eradicating pathogens, and also understand how the immune responds to HPIV infections. 

Understanding parainfluenza infection 

Parainfluenza virus, more commonly known as the human parainfluenza virus (HPIV), is a single-stranded RNA virus. It belongs to the Paramyxoviridae family and consists of four main types: HPIV-1, HPIV-2, HPIV-3 and HPIV-4. HPIV infection is usually mild (in adults), and an individual can be reinfected several times throughout their lives, but it can also be severe at times when hospitalisation might be required. Severe illnesses often occur in younger children (below the age of 5), infants, immunocompromised individuals and the elderly.¹ 

This virus is known to have a worldwide prevalence, contributing to multiple outbreaks throughout the year. Specifically, each HPIV type initiates an epidemic following different patterns and in different seasons. For instance, besides its sporadic occurrence throughout the year, HPIV-3 outbreaks are generally observed in spring, whereas HPIV-1 and HPIV-2 contribute to outbreaks in autumn biennially.² 

Like the common cold, HPIV is mainly transmitted via direct contact with respiratory droplets from an infected individual or droplet transmission within a short range; in some cases, airborne transmission can be possible.² HPIV infections display very similar symptoms to the common cold such as:

• Fever
• Sore throat 
• Cough
• Sneezing
• Runny/Blocked nose 
• Difficulty in breathing

HPIV infections can also lead to many other types of upper and lower tract respiratory infections (URTI and LRTI), especially in the high-risk groups mentioned above.³ For example:

• Otitis media
• Pneumonia
• Croup
• Bronchitis
• Pharyngitis
• Conjunctivitis

The innate immune response 

Our immune system is an intricate system that involves the collaboration between different cells, organs and tissues to help the body fight infection-causing pathogens. The immune system consists of two arms: innate and adaptive immunity. 

The innate immune system acts as the first line of defence against pathogens. The innate immunity modulates immune responses by pathogen detection via pattern recognition receptors (PRR), followed by initiating non-specific immune responses such as phagocytosis and cytokine production to eliminate invading pathogens immediately and effectively. Besides that, innate immunity also plays a part in stimulating the adaptive immune response for the development of immunological memory and a more specific immune response in the event of a secondary infection.⁴ 

Neutrophils, macrophages, basophils, eosinophils,  dendritic cells, mast cells and natural killer cells (NK cells) are some examples of innate immune cells. They all have different roles in modulating immune responses. For instance, neutrophils and macrophages are responsible for the phagocytosis of pathogens and dead cells, thus, promoting efficient clearance of ‘non-self’ pathogens that are present in the body. Eosinophils, basophils and mast cells are primarily involved in allergic inflammatory responses and parasitic infections (eosinophils and mast cells only).⁵ 

NK cells function to prevent the dissemination of cancer cells and viruses by inducing apoptosis of infected cells via the secretion of granzymes and perforin. Dendritic cells, on the other hand, are unique in the sense that they are involved in both innate and adaptive arms of the immune system. Not only do they possess a phagocytic trait, but they are also known as antigen-presenting cells (APC), where they present the antigen to adaptive immune cells to activate the secondary immune response. Hence, they are often known as the modulators that bridge the innate and adaptive arms of the immune system.⁵

Another vital part of innate immunity is the complement system. The complement system presents a hybrid of inflammatory responses, including the direct destruction of pathogens and the opsonisation of pathogens to promote the phagocytic actions of innate immune cells. It also resembles the function of dendritic cells as it enhances the presentation of antigens to the adaptive immune cells, thus contributing to the coordination between both innate and adaptive arms of the immune system.⁶  

The adaptive immune response 

Conversely, the adaptive immune system is an antigen-specific, long-lasting immune response. Both innate and adaptive arms of the immune system complement each other when there is an infection. As mentioned earlier, the innate immune response often takes place immediately after the infection is detected. The adaptive immune response usually sets off several days after the infection.⁷ 

Adaptive immunity activates secondary immune responses when the host is infected by the same pathogen again. This is due to the ability of adaptive immune cells to develop long-term immunological memory. Hence, the specific pathogen can be eliminated swiftly upon repeated infections. Adaptive immune cells include T cells that are capable of identifying infected host cells and ‘non-self’ antigens taken up by APCs, and B cells that function to produce antibodies against specific antigens directly, without the help of APCs.⁵

The ability of T cells to recognise foreign antigens lies in the interaction between T-cell receptors (TCRs) expressed on T cell membranes and the APCs. The membranes of APCs express a group of glycoproteins called major histocompatibility complex (MHC) molecules, which are further categorised into MHC class 1 and MHC class 2 molecules.  These two classes bind to antigen fragments that are either synthesised endogenously (MHC class 1) or exogenously (MHC class 2). TCRs that are compatible with the specific antigen then bind to the MHC-antigen complex to induce the differentiation of naïve T cells to CD8+ (cytotoxic T cells) or CD4+ T cells (Helper T cells). For instance, MHC class 2 molecules stimulate the formation of CD4+ T cells which are crucial in mediating immune responses via the release of cytokines, while MHC class 1 molecules activate CD8+ T cells, which are mainly involved in the ‘killing’ of infected host cells.^5,7 

The activation pathway of B cells differs in the sense that the B-cell receptors (BCR) can bind to specific antigens directly, leading to a series of downstream events, including the differentiation and proliferation of B cells into plasma cells or memory B cells. Plasma cells produce antibodies, while memory B cells contribute to long-lasting immunological memory. Due to its long-lived trait, memory B cells do not undergo apoptosis; instead, they develop ‘memory’ during the first infection, so they can respond quickly by producing antibodies during the second infection, thus providing long-term protection against the pathogen. With that being said, B cells are said to be the primary regulator of humoral immunity.⁵

Immune evasion strategies by parainfluenza virus

The complex interplay between innate and adaptive immunity is the key to successful eradication of an infection. The same goes for the elimination of HPIV infection. The invasion of HPIV triggers both innate and adaptive immune responses. However, humoral immunity acts as the primary modulator against HPIV.⁸ Antibodies with neutralising effects, predominantly serum IgG and mucosal IgA antibodies target the surface glycoproteins, hemagglutinin-neuraminidase (HN) and fusion (F) proteins of HPIV, thus providing long-lasting protection against HPIV reinfection.⁹ Cell-mediated immunity mediated by T cells essentially inhibits the replication of HPIV and is said to provide a shorter duration of protection than humoral immunity.¹⁰  

Despite the long-term immunity provided by antibodies after primary infection, reinfection can still occur throughout their lives, although the symptoms are usually milder than the first infection. One of the reasons could be the inefficiency in preserving the protective levels of IgG and IgA antibodies in the respiratory lumen throughout life, thus resulting in the reoccurrence of HPIV-induced URTI.⁹ 

Another explanation is the evolution of HPIV, which results in successful immune evasion.  The virus produces an accessory protein, V protein, that is capable of impeding the host’s viral RNA sensing and interferon production mechanism, which then enables the virus to escape from the immunosurveillance system. Moreover, parainfluenza viruses also evolved in a way to avoid the complement system. The virus integrated host proteins CD46 and CD55, which are proteins that act to block the complement pathway, into their viral envelope. That way, the virus could spare themselves some time to replicate and spread in the host.⁸

Vaccination and antiviral treatments 

There are currently no antiviral treatments or vaccines available to prevent HPIV infections. However, a live-attenuated HPIV-3 vaccine adapted at low temperatures seems to show significant immunogenic responses even when tested in children of a month old.¹¹ This vaccine appears to be a feasible approach, but further research is required to justify its efficacy as a potential intervention.  

A potential antiviral agent against HPIV, which is still under research to assess its clinical feasibility, aims to disrupt viral entry by removing the binding site of the virus’s HN protein. This approach involves the usage of a recombinant sialidase protein, DAS18, which functions to remove the sialic acid receptors. It is suggested that this desialylation approach demonstrated positive anti-HPIV results in a cotton rat HPIV-infected model.⁸

Summary

It is fairly common for an individual, young or old, to contract an HPIV infection at least once throughout their lives. The disease is usually mild in most healthy individuals, but one might suffer from severe symptoms if they have a weakened immune system. Also, HPIV infections contribute to the occurrence of chronic UTRI and LTRI, especially among high-risk patients.

Our immune system plays a huge role in counteracting the infection, thus resulting in long-term protection against the virus. That is why patients who have been diagnosed with HPIV infection beforehand usually experience milder symptoms in the event of reinfection. Further research on the virus-host interactions and their capability to evade the immune system is required in hopes of developing vaccines and treatments to prevent HPIV infections and the consequences that follow.