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Nutrition, immunity and COVID-19 BMJNPH: first published as 10.1136/bmjnph-2020-000085 on 20 May 2020. Downloaded from
Philip C Calder
To cite: Calder PC. Nutrition, AbsTrACT substrates for biosynthesis and regulatory
immunity and COVID-19. BMJ The immune system protects the host from pathogenic molecules. These energy sources, substrates
Nutrition, Prevention & Health organisms (bacteria, viruses, fungi, parasites). To deal with and regulatory molecules are ultimately
2020;3:e000085. doi:10.1136/ this array of threats, the immune system has evolved to derived from the diet. Hence an adequate
bmjnph-2020-000085 include a myriad of specialised cell types, communicating
School of Human Development molecules and functional responses. The immune system supply of a wide range of nutrients is essen-
and Health, Faculty of Medicine, is always active, carrying out surveillance, but its activity tial to support the immune system to func-
1 2
University of Southampton, is enhanced if an individual becomes infected. This tion optimally. At the time of writing, the
Southampton, UK heightened activity is accompanied by an increased rate world is in the grip of a pandemic caused
Correspondence to of metabolism, requiring energy sources, substrates for by infection with a new coronavirus called
Dr Philip C Calder, Human biosynthesis and regulatory molecules, which are all severe acute respiratory syndrome corona-
Development and Health, ultimately derived from the diet. A number of vitamins (A, virus 2 (SARS-CoV -2); the illness associated
Faculty of Medicine, University B6, B12, folate, C, D and E) and trace elements (zinc, copper, with infection by SARS-CoV -2 is called coro-
of Southampton, Southampton, selenium, iron) have been demonstrated to have key roles navirus disease discovered in 2019 or COVID-
UK; pcc@ soton. ac. uk in supporting the human immune system and reducing 19.3 4 The aim of this article is to summarise
risk of infections. Other essential nutrients including other the role of specific nutrients in supporting
Received 14 April 2020 vitamins and trace elements, amino acids and fatty acids the immune system, particularly, but not
Accepted 30 April 2020 are also important. Each of the nutrients named above has exclusively, with regard to antiviral defences.
Published Online First roles in supporting antibacterial and antiviral defence, but The roles of nutrition in overcoming gut
20 May 2020 zinc and selenium seem to be particularly important for the microbial dysbiosis and in calming a so- called
latter. It would seem prudent for individuals to consume ‘cytokine storm’ will also be discussed. First,
sufficient amounts of essential nutrients to support
their immune system to help them deal with pathogens some features of coronaviruses and of the
should they become infected. The gut microbiota plays immune system will be described.
a role in educating and regulating the immune system.
Gut dysbiosis is a feature of disease including many Coronaviruses
infectious diseases and has been described in COVID-19. Coronaviruses are a large group of single- http://nutrition.bmj.com/
Dietary approaches to achieve a healthy microbiota can stranded RNA viruses that are common
also benefit the immune system. Severe infection of 5 6
the respiratory epithelium can lead to acute respiratory among mammals and birds. Coronavi-
distress syndrome (ARDS), characterised by excessive ruses cause respiratory and, less frequently,
5
and damaging host inflammation, termed a cytokine gastrointestinal diseases. The respiratory
storm. This is seen in cases of severe COVID-19. There symptoms caused by coronaviruses can range
is evidence from ARDS in other settings that the cytokine from common cold-like or mild influenza-
storm can be controlled by n-3 fatty acids, possibly like symptoms to severe pneumonia. In
through their metabolism to specialised pro- resolving December 2019, a new type of coronavirus on January 4, 2023 by guest. Protected by copyright.
mediators. causing pneumonia and death was identified
3 4
in Wuhan, China ; this new coronavirus is
called SARS-CoV -2 because it is genetically
InTroduCTIon similar to SARS-CoV which caused the 2002
The immune system exists to protect the host outbreak of severe acute respiratory distress
from noxious environmental agents espe- syndrome (ARDS). In fact, SARS-CoV -2 is
7
cially pathogenic organisms, which may be in the seventh known human coronavirus.
the form of bacteria, viruses, fungi or para- However, SARS-CoV -2 is new to the human
sites. To deal with such an array of threats, immune system and so there was no under-
the human immune system has evolved to lying existing natural immunity against
include a myriad of cell types, communi- it. This is probably why SARS-CoV -2 has
cating molecules and functional responses. spread so rapidly. SARS- CoV-2 infects respi-
© Author(s) (or their The immune system is always active, carrying ratory epithelial cells causing the symptoms
employer(s)) 2020. Re- use out surveillance, but its activity is enhanced if described above, and in severe cases requires
permitted under CC BY- NC. No an individual becomes infected. This height- ventilatory support. Older people, especially
commercial re- use. See rights ened activity is accompanied by an increased those with existing morbidities like diabetes,
and permissions. Published by
BMJ. rate of metabolism, requiring energy sources, cardiovascular disease, respiratory disease and
74 Calder PC. bmjnph 2020;3:e000085. doi:10.1136/bmjnph-2020-000085
BMJ Nutrition, Prevention & Health
hypertension, are particularly susceptible to severe symp- Barrier function BMJNPH: first published as 10.1136/bmjnph-2020-000085 on 20 May 2020. Downloaded from
toms and mortality, as are individuals with suppressed The barrier function of the immune system acts to prevent
3 4 pathogens from entering the body from the external envi-
immune systems. There is currently no treatment for
infection with SARS- CoV-2 or for COVID-19. Current ronment. This includes physical barriers like the skin and
strategies aim to limit the spread of the virus by preventing mucosal layers (gastrointestinal tract, respiratory tract,
contact between people. The search for vaccines to offer genitourinary tract); chemical barriers like the acid pH
immune protection against SARS-CoV -2 and for pharma- of the stomach; and biological barriers like the presence
cological treatments to prevent the virus from replicating of commensal organisms on the skin and in the intestinal
is underway. In the meantime, approaches to ensure that tract, secretions like IgA and antimicrobial proteins in
individuals’ immune systems are well supported should saliva and tears, and the complement system.
be taken. Nutrition should be at the forefront of these
approaches. Identification of pathogens
Pathogens are recognised by cells of the innate immune
The immune system system, such as macrophages, monocytes and dendritic
Introductory comments cells. This is achieved through the presence of pattern
The immune system becomes vital once an individual is recognition receptors (PRRs) that recognise general
exposed to an infectious agent. However, the nature of molecular structures that are broadly shared by groups
infectious agents varies and so different approaches are of pathogens. These structures are termed microbe-
required by the immune system to deal with different associated molecular patterns or MAMPs. When PRRs
types of infectious agent. These different approaches recognise MAMPs, the first line of host defensive
follow similar general strategies, which aim to seek out responses is activated. PRRs include Toll-like receptors
and destroy, but the precise immune mechanisms involved (TLRs). More than 10 functional TLRs have been identi-
can differ. For example, most bacteria do not invade host fied in humans, each one detecting distinct MAMPs from
cells and remain accessible to the host’s immune system; bacteria, viruses, fungi and parasites. The best described
often these bacteria will be engulfed by innate phagocytic of these are TLR4 which recognises the lipopolysaccha-
cells (typically neutrophils, monocytes, macrophages, rides from the cell wall of Gram-negative bacteria and
dendritic cells), killed within intracellular phagocytic TLR2 which recognises the lipoteichoic acid from the cell
vacuoles and then digested. Remnants of the digested wall of Gram- positive bacteria. Several TLRs are expressed
bacteria (antigens) can then be displayed via major histo- on the cell surface of innate immune cells because the
compatibility class (MHC) II on the surface of the phago- pathogens they recognise, mainly bacteria, are extracel-
cyte. These antigens are recognised by antigen- specific lular. Because viruses enter host cells, it is important that
+ there are also intracellular TLRs. Indeed, intracellular
CD4 helper T lymphocytes and this triggers the acquired TLRs that recognise viral DNA, viral double-stranded http://nutrition.bmj.com/
(also called adaptive) immune response to the bacteria, RNA and viral single- stranded RNA exist. Among these,
which involves the orchestrating T lymphocytes, B TLR7 and TLR8 are found in macrophages, monocytes,
lymphocytes (which produce antigen- specific antibodies) dendritic cells and some other cell types and are likely to
and the further activation of innate immune cells. This be important in innate recognition of the single- stranded
response to extracellular bacteria is clearly targeted at RNA of coronaviruses. However, proteins, including the
killing those bacteria. Viruses (and some bacteria) invade spike glycoprotein, of the coronavirus coat are also likely
host cells rather than remaining exclusively extracellular; to be recognised by both intracellular and extracellular
this can trigger presentation of antigens via MHC I on the 8–11 on January 4, 2023 by guest. Protected by copyright.
surface of the infected cells. Recognition of these anti- PRRs.
+
gens by CD8 cytotoxic T lymphocytes results in killing Elimination of pathogens
of the host cell that is presenting the antigen. Natural As mentioned earlier, extracellular bacteria can be
killer cells also recognise virally infected cells and act in engulfed by phagocytic cells that include macrophages
an analogous way to cytotoxic T lymphocytes by killing and dendritic cells. After digestion of internalised bacteria,
the infected cells. Thus, this response to virally infected peptide fragments, termed antigens, are presented on the
cells is targeted at killing the host cells that harbour surface of the phagocytic cells (via MHC II) to antigen-
viruses. Killing host cells of course liberates viruses and +
specific CD4 helper T lymphocytes. The activated helper
the battle between host immune cells and virally infected T lymphocytes (specifically the T helper 1 phenotype)
cells continues. proliferate and produce cytokines including interleukin
There are four general functions of the immune system (IL)-2 and interferon (IFN)-γ. IFN-γ promotes antigen-
that enable effective host defence: specific antibody production by B lymphocytes. These
1. Creating a barrier to prevent pathogens from entering antibodies coat the bacteria, neutralising them and
the body. making the process of phagocytosis more efficient.
2. Identifying pathogens if they breech a barrier. In parallel with phagocytosis, innate immune cell
3. Eliminating pathogens. recognition of pathogens via PRRs triggers inflamma-
4. Generating an immunological memory. tory signalling, activation of transcription factors like
Calder PC. bmjnph 2020;3:e000085. doi:10.1136/bmjnph-2020-000085 75
BMJ Nutrition, Prevention & Health
BMJNPH: first published as 10.1136/bmjnph-2020-000085 on 20 May 2020. Downloaded from
Figure 1 Overview of antiviral immunity. The events in the figure are explained in the text. B, B lymphocyte; CTL, cytotoxic
T lymphocyte; IFN, interferon; Ig, immunoglobulin; IL, interleukin; MHC, major histocompatibility class; NFκB, nuclear factor
kappa- light- chain- enhancer of activated B cells; NK, natural killer cell; Th, helper T lymphocyte; TLR, Toll-like r eceptor; TNF,
tumour necrosis factor.
nuclear factor kappa- light- chain- enhancer of activated B antigen that the body has previously encountered and
cells (NFκB), inflammasome assembly, and production of initiate a corresponding immune response. There are
classic inflammatory cytokines like tumour necrosis factor two aspects of immunological memory. First, antibodies
(TNF), IL-1β and IL-12. Viral infection of some cell types can persist in the circulation for many months to many http://nutrition.bmj.com/
promotes release of type 1 IFNs (IFN-α and IFN-β) and years, providing protection against reinfection. Second,
these induce antiviral resistance, in part through activa- after the cessation of an active immune response, a small
12 13 + +
tion of natural killer cells. Furthermore, as explained number of memory T (both CD4 and CD8 ) and B
earlier, virally infected cells directly activate natural killer lymphocytes remain; they are in a resting state but if they
cells which act to kill the infected cell. In addition, PRR encounter the same antigen that triggered their forma-
signalling induces maturation of dendritic cells which are tion they are able to respond immediately and lead to
responsible for viral antigen processing and presentation, rapid elimination of the source of the antigen. Memory on January 4, 2023 by guest. Protected by copyright.
so initiating acquired immunity. Upregulation of MHC I cells have a long life (up to several decades). Immunolog-
on virally infected cells including both respiratory epithe- ical memory is the basis of vaccination.
lial cells and dendritic cells results in presentation of viral
+ Effect of ageing on the immune system
antigens to CD8 cytotoxic T lymphocytes. This activates
them to kill virally infected cells through the release of Ageing can be associated with a loss of immune compe-
14–18
pore forming proteins like perforin. Presentation of viral tence, a process called immunosenescence. The
antigens via MHC II and the cytokine milieu lead to the features of immunosenescence are shown in box 1.
+ One factor linked to immunosenescence is decreased
activation of CD4 helper T lymphocytes with switching to
the T helper 1 phenotype. These cells produce IL-2, which output of immune cells from bone marrow, the site of
promotes cytotoxic T lymphocyte activity, and IFN-γ, which origin of all immune cells. In addition, involution of the
promotes differentiation of B lymphocytes to plasma cells thymus with age decreases output of naive T lympho-
which produce antiviral antibodies. These antibodies cytes, resulting in reduced capacity to respond to new
can bind to free viruses neutralising them. The processes antigens. Immunosenescence means that, compared
involved in antiviral immunity are summarised in figure 1. with younger adults, older people have increased
susceptibility to infections including respiratory tract
Immunological memory infections and pneumonia and poorer responses to
14 15 19 20
Immunological memory refers to the ability of the vaccination. The gut mucosa is the largest site
immune system to quickly and specifically recognise an of immune tissue in humans and senescence of the
76 Calder PC. bmjnph 2020;3:e000085. doi:10.1136/bmjnph-2020-000085
BMJ Nutrition, Prevention & Health
box 1 some key features of age- related immune decline disease (diabetes, non-alcoholic fatty liver disease), BMJNPH: first published as 10.1136/bmjnph-2020-000085 on 20 May 2020. Downloaded from
23
(immunosenescence) neurodegeneration and some cancers and may predis-
pose to mounting an excessive inflammatory response
T lymphocytes when infected. Although inflammation is part of the
► Decreased numbers in the circulation. innate immune response and innate and acquired
► Imbalances among different phenotypes. immunity should work in a coordinated and integrated
► Decline in naive T lymphocyte production and numbers. way (see figure 1), an excessive inflammatory response
► Accumulation of non- functional memory T lymphocytes. can lead to impairments in acquired immunity.23
► Diminished antigen receptor diversity.
► Impaired responsiveness. Effect of obesity on the immune system
► Impaired proliferation. Obesity can be associated with a loss of immune compe-
► Impaired production of cytokines like interleukin (IL) 2 and interferon 24 25
(IFN)-γ. tence, with impairments of the activity of helper T
b lymphocytes lymphocytes, cytotoxic T lymphocytes, B lymphocytes and
26–28
► Decline in naive B lymphocyte numbers. natural killer cells, and reduced antibody and IFN-γ
26 27
► Accumulation of non- functional memory B lymphocytes. production. This means that, compared with healthy
► Impaired responsiveness. weight individuals, the obese have increased susceptibility
24 29–31
► Altered balance of immunoglobulins. to a range of bacterial, viral and fungal infections,
dendritic cells and poorer responses to vaccination.26 31 The impact of
► Decreased phagocytosis. obesity has been well explored in relation to influenza
► Decreased Toll- like receptor (TLR) expression. infection and vaccination against influenza. During the
► Decreased responsiveness. 2009 H1N1 influenza A virus pandemic, obese individuals
► Decreased type 1 IFN production. showed delayed and weakened antiviral responses to infec-
neutrophils tion and showed poorer recovery from disease compared
26
► Numbers in the circulation are preserved. with healthy weight individuals. Animal studies and
► Impaired chemotaxis. case studies in humans show that obesity is associated
► Impaired oxidative burst and bacterial killing. with prolonged shedding of influenza virus, indicating
► Impaired phagocytosis. an impairment in viral control and killing, and the emer-
► Decreased TLR expression. 26 32
► Decreased production of neutrophil extracellular traps. gence of virulent minor variants. Green and Beck note
► Decreased responsiveness. that compared with healthy weight individuals, vacci-
nated obese individuals have twice the risk of influenza or
Monocytes influenza- like illness, indicating poorer protection from
► Altered TLR expression. vaccination in the obese. Sheridan et al33 investigated http://nutrition.bmj.com/
► Decreased responsiveness. the responses of immune cells from the blood of healthy
► Altered pattern of cytokine production. weight, overweight and obese individuals to the influenza
Macrophages vaccine in vitro. Exposure of the blood immune cells to
► Impaired phagocytosis. the vaccine increased the number of activated cytotoxic
► Altered TLR expression. T lymphocytes, the number of granzyme expressing cyto-
natural killer cells toxic T lymphocytes and the number of IFN-γ producing
► Increased numbers in the circulation. cytotoxic T lymphocytes. However, the responses of cells on January 4, 2023 by guest. Protected by copyright.
► Imbalances among different phenotypes. from obese individuals were blunted by 40%, almost 60%
► Impaired cytotoxicity. and 65%, respectively. Cells from overweight individ-
► Impaired responsiveness. uals showed responses intermediate between those from
► Impaired production of cytokines. healthy weight and obese individuals. Similar findings for
the response of blood cells to the pandemic H1N1 influ-
34
enza A virus were reported by Paich et al. Paradoxically,
gut mucosal immune system has been demonstrated obesity is also linked to an increase in blood concentra-
in murine models, with reductions in secretory IgA tions of many inflammatory mediators, a state of chronic
35
responses, impaired oral tolerance to new antigens and low- grade inflammation. This state is considered to
impaired mucosal dendritic cell function, as reviewed contribute to an increased risk of chronic conditions of
21 22 35
elsewhere. Immunosenescence may be one factor ageing and may predispose to mounting an excessive
that predisposes older people to more severe COVID- inflammatory response when infected. Thus, obesity may
19. Paradoxically, ageing is also linked to an increase in be one factor that predisposes to more severe COVID-19;
blood concentrations of many inflammatory mediators, in support of this, a French report found that 85.7% of
23 SARS- CoV-2 infected obese individuals required mechan-
a situation termed inflammageing. This state is consid-
ered to contribute to an increased risk of chronic condi- ical ventilation compared with 47.1% of infected healthy
36
tions of ageing like cardiovascular disease, metabolic weight individuals.
Calder PC. bmjnph 2020;3:e000085. doi:10.1136/bmjnph-2020-000085 77
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