Mucosal Immunity and acute viral gastroenteritis

Abstract

Acute gastroenteritis is a major killer of the very young worldwide. Rotavirus is the most common intestinal virus, causing acute gastroenteritis and extra-intestinal complications especially in young and chronically ill subjects. As early as 1991, the WHO recommended as high priority the development of a vaccine against rotavirus, the major pathogen causing enteric infections. Since the introduction of rotavirus vaccines for infant immunization programmes in different parts of the world in 2006, vaccination against rotavirus has resulted in substantial declines in severe gastroenteritis. The oral rotavirus vaccines RotaTeq^® and Rotarix^® are excellent examples for their unique features and principles of mucosal immunization. We elaborate on rotavirus immunity and the success of rotavirus vaccination and aspects also beyond infants’ acute gastroenteritis.

Keywords: :

• mucosal
• gastroenteritis
• rota-virus
• diarrhea
• young
• elderly
• immunization

Introduction

Acute gastroenteritis is a major killer of the very young worldwide contributing to about 1.8 million deaths annually. Rotavirus is the most common intestinal virus, causing acute gastroenteritis especially in young and chronically ill subjects. As early as 1991, the WHO recommended as high priority the development of a vaccine against rotavirus, the major pathogen causing enteric infections. Following the withdrawal for safety reasons of a reassortant tetravalent rotavaccine in the 1990s, ongoing unacceptably high morbidity and mortality from rotavirus infection has resulted.

In response to the continuing health risk from acute gastroenteritis, especially in young and chronically ill subjects, two newly developed rota vaccines; RotaTeq^® and Rotarix^®, were launched in 2006. These new vaccines finally provided a solution for a major public health problem in both non-industrialized and industrialized countries.

Rotavirus Vaccines: State of the Art

RotaTeq^® (RV5) (Merck Vaccines) is a genetically reassortant pentavalent live vaccine with an apathogenic bovine rotavirus as backbone and the immunity-inducing genetic features of the five most prevalent human rotavirus serotypes. In contrast, Rotarix^® (RV1) (GlaxoSmithKline Biologicals) is a live attenuated vaccine containing the most prevalent serotype G1.

A recent Cochrane review evaluated rotavirus vaccines approved for preventing rotavirus diarrhea. This review included more than 34 placebo-controlled studies with more than 180 000 vaccinees. It demonstrated a consistent reduction in severe and any rotavirus gastroenteritis, associated hospitalizations and emergency department consultations combined with good tolerability and safety profile.¹⁴ An unexpected additional benefit was also noted; while the reduction of rotavirus disease in the immunised groups confirmed the efficacy of the rota vaccines, a decrease of any severe diarrhea was observed as well. To understand this phenomenon, rotavirus infection and the immunological background of this oral immunization should be considered.

Gastrointestinal Mucosal Immunity

The human body has a mucosal surface of more than 400 m² which acts as a frontier to the environment; this is where pathogens initiate their replication process. Therefore, an induction of immune responses at this mucosal border is critical in preventing potentially dangerous infections. Immunity at mucosal sites protects the host by inhibiting microbial entry into mucosal epithelial cells (ECs). Mucosal antibodies can also inhibit the activity of many aggressive microbial enzymes and toxins in the lumen and neutralize mucosal viruses inside ECs.² Mucosal antibodies of immunoglobulin A (IgA) and immunoglobulin G (IgG) isotype can evoke cytotoxic effects, lysing infected cells via eosinophilic and neutrophilic granulocytes and natural killer cells.⁹ For intracellular microbes, mucosal IgG can mediate opsonization and internalization of the pathogens by phagocytes, this result in pathogen destruction or the presentation of pathogen-derived antigens which activates multiple types of mucosal effector T-cell responses, promoting pathogen containment or clearance.² The “mucosa associated lymphoid tissue” (MALT) also encompasses distal components, called “gut-associated lymphoid tissue” (GALT). Immunization strategies targeting the GALT predominantly elicit protective responses in gastrointestinal structures.⁵ In GALT, antibody responses mainly involve IgA, activating follicular B-cells, and CD4⁺ T-cells expressing CD40 ligand.⁷ Most IgA-producing plasma cells emerge from mesenteric lymph nodes and the germinal centers (GCs) of Peyer’s patches with their cellular composition and cytokine environment favoring IgA production. One of the major functions of GCs in lymphatic follicles is the generation of memory/effector B-cells to produce antibodies directed against T-cell-dependent antigens. Thus, MALT potentially generates adaptive high affinity and specific pathogen-directed responses. It is known from human and animal studies that the lamina propria also has the cellular and molecular prerequisites to induce IgA production independently of T-cells and other lymphatic tissue.⁸

Rotavirus and Host Immunity

Under normal physiological conditions, IgA is critical in immune responses to pathogens that invade and cause disease at any mucosal surfaces such as the gastrointestinal tract. It mediates its effector function via interactions with mucosal epithelial cells, binding to a receptor, and high and low affinity antigen binding. Viral replication takes place in the absorptive epithelial cells of the small intestine. Secretory and fecal IgA are necessary for the clearance of rotavirus infection and the protection from re-infection with rotavirus.¹ Rotavirus is commonly present in the systemic circulation during intestinal infection, irrespective of this IgA plays only a minimal role in clearance of the virus from the blood and is not essential for protective immunity against systemic virus upon re-exposure to the virus. Systemic IgG or immunoglobulin M (IgM) are the important B-cell effector products clearing the systemic virus from the blood. This is not unexpected as rotavirus infection induces substantially higher levels of serum IgG than IgA. In addition, IgG plays a key role in clearance of rotavirus in the blood and in protection against antigenemia and viremia upon re-exposure.

Besides inducing rotavirus-specific IgA, oral mucosal rotavirus immunization obviously induces IgA in general as well. It has been speculated that the observed decrease of any acute gastroenteritis was due to this stimulation. In addition, mixed viral infections are often responsible for acute gastroenteritis. When preventing rotavirus infection, the immune system might be better able to cope with other pathogens, controlling other gastrointestinal viruses (e.g., adenovirus, norovirus).

The Role of Rotavirus Immunization Beyond Infant Acute Gastroenteritis

In the recent years, it has been suggested that rotavirus is responsible for more infections other than acute gastroenteritis alone. A prospective study performed in Germany clearly demonstrated rotavirus not only as a major source of nosocomial infections, but also responsible for extra-intestinal morbidity such as encephalopathy or acute renal failure.¹³ Rotavirus has also been isolated from cerebrospinal fluid in children with rotavirus infection. On this background, a recent finding from the USA is remarkable; a full course of rotavirus vaccination was statistically associated with an 18–21% reduction in risk of seizure requiring hospitalization or emergency department care in the year following vaccination, compared with unvaccinated children. This demonstrates that rotavirus immunization not only directly prevents systemic rotavirus infection, including extra- intestinal complications involving the central nervous system,³ but also prevents secondary effects of rotavirus infection such as rotavirus-related elevation of nitric oxide in cerebrospinal fluid inducing neurotoxicity,^4,16 and/or calcium channel fluctuations resulting in neurotransmitter dysregulation.¹⁵ This reduction in childhood seizures complements the well-documented vaccine related benefit of a reduction in the number of patients hospitalized in the US due to diarrhea caused by rota-virus.¹¹

Rotavirus disease is also a major health concern for the elderly. In a retrospective study performed at a large tertiary hospital in Germany, 12% of patients hospitalized for acute gastroenteritis were over 65 y of age.¹² The elderly population is particularly vulnerable due to waning immunity. A very recent study assessed the safety and immunogenicity of RV5 in 65–80 y old adults. Encouragingly, immune responses (serum anti-rotavirus IgA and serum neutralizing antibodies against human rotavirus serotypes in the vaccine) rose in this population after a single dose of RV5, despite their older age and pre-existing rotavirus-specific antibodies.¹⁰

In conclusion, rotavirus immunization by oral vaccines is effective in providing protection from rotavirus disease, a major public health problem extending beyond diarrhea alone.

Abbreviations:
ECs	=	epithelial cells
GALT	=	gut-associated lymphoid tissue
GCs	=	germinal centres
GI	=	gastrointestinal
IgA	=	Immunoglobulin A
IgG	=	Immunoglobulin G
IgM	=	Immunoglobulin M
MALT	=	mucosa associated lymphoid tissue
WHO	=	World Health Organization

Disclosure of Potential Conflicts of Interest

No potential conflicts of interest were disclosed.

*Correspondence to: Markus Rose; Email: AUTHOR PLEASE PROVIDE CONTACT INFO

AUTHOR PLEASE ADD SUBMITTED/ACCEPTED DATES

10.4161/hv.29605