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Friday 8 November 2019
Wednesday 3 April 2019
Innate and adaptive immune response to virus
Abstract
The host counters a viral infection
through a complex response made up of components belonging to both the innate
and the adaptive immune system. In this report, we review the mechanisms
underlying this response, how it is induced and how it is co-ordinated. As
cell-cell communication represents the very essence of immune system
physiology, a key to a rapid, efficient and optimally regulated immune response
is the ability of the involved cells to rapidly shift between a stationary and
a mobile state, combined with stringent regulation of cell migration during the
mobile state. Through the co-ordinated recruitment of different cell types
intended to work in concert, cellular co-operation is optimized particularly
under conditions that may involve rare cells. Consequently, a major focus is
placed on presenting an overview of the co-operative events and the associated
cell migration, which is essential in mounting an efficient host response and
co-ordinating innate and adaptive immunity during a primary viral infection.
Introduction
Viruses are infectious pathogens that
exploit the host's cellular machinery for their survival and replication. The
host defence against viral infection consists of a complex interplay between
components of the innate and the adaptive immune system. The innate immune
response represents a rapid first line of defence, but it is often insufficient
by itself to clear or permanently control a viral infection. However, innate
immune mediators play a very important role in keeping the virus load low until
a specific, adaptive immune response can be generated. Equally important,
components of the innate response shape the adaptive immune response and direct
the subsequent effector phase. Indeed, it is justified to state that an appropriate
innate response is the foundation upon which host survival depends.
The innate immune system comprises
several cell types, including dendritic cells (DCs), monocytes/macrophages and
natural killer (NK) cells, which, besides constraining the virus spread and
eliminating virus‐infected cells, secrete high levels of proinflammatory
cytokines and chemokines, which direct not only the activation and
differentiation of the adaptive immune response but also the subsequent
recruitment of antigen‐primed effector T cells to the sites of viral
replication. The adaptive immune response towards viruses is mediated by T and
B cells expressing clonally distributed, antigen‐specific receptors. T and B
cells are activated and differentiate in the secondary lymphoid organs (SLO)
through an interplay between several cell types of both the innate and the
adaptive immune system including professional antigen‐presenting cells (APC).
DCs are a specialized family of APCs that effectively link innate recognition
of invading pathogens to the generation of the appropriate type of adaptive
immune response . During viral infection, they play a key role in sensing and
processing viral information and directing the differentiation of naïve T and B
cells to virus‐specific effector T cells and antibody‐secreting plasma cells.
Although other cell types, such as macrophages or activated parenchymal cells,
may serve as APCs activating primed T cells, DCs are probably the only class of
APCs that effectively activate naïve T cells. DCs reside in essentially any
tissue in an immature form, and during viral infection they become activated
either upon a direct viral encounter or through interaction with other local
cells of the innate immune system secreting cytokines and chemokines. Following
activation in a peripheral site, the activated DCs migrate towards the regional
draining lymph nodes by means of the afferent lymphatics. In the SLO, antigen
is presented by professional APCs to rare antigen‐specific T and B cells that
eventually become activated; subsequently, these may interact to regulate the
induced adaptive responses, e.g. the generation of a T helper cell‐dependent
antibody response. While antibodies are rapidly distributed throughout the
accessible fluid phase of the host, T cells require close contact with APCs to
perform their effector function. Once activated, T cells are therefore released
into the blood stream, and from the circulation activated T cells are directed
to areas of inflammation to exert their antiviral effector function.
From the above brief description of
how the immune response unfolds during a primary viral infection, it is
immediately evident that mechanisms controlling leucocyte mobility and
migration play a key role in deciding the efficiency of the induced immune
response. For this reason, the study of factors regulating the expression of
adhesion molecules and their interaction with matching ligands has become a
central area of research in infection immunology. While the expression of
adhesion molecules – in particular members of the integrin family e.g. LFA‐1
and VLA‐4 – on the leucocyte surface is determined by their type and state of
differentiation, the expression of relevant vascular ligands and the affinity
between the two is strongly influenced by local signals present in the involved
tissue. Thus, cytokines control the state of endothelial activation and in this
manner the expression of relevant ligands for the adhesion molecules expressed
by circulating leucocytes.
Chemokines, on the other hand, regulate
the affinity of integrin binding to their matching ligands of the
immunoglobulin (Ig) superfamily (ICAM‐1 and VCAM‐1) expressed by activated
endothelium. In this manner, these secreted mediators regulate which cells are
recruited to which sites, e.g. the draining lymph nodes, sites of inflammation
and/or other relevant tissues in the host. Importantly, the local production of
cytokines and chemokines is strongly influenced by cells of the innate immune
system such as neutrophils, monocytes/macrophages, DCs and NK cells. An optimal
activation of the innate immune system is therefore believed to be important
not only for the generation of the antigen‐specific effector cells but also in
shaping the inflammatory exudate, which represents the foundation for efficient
elimination of most invading pathogens as well as any associated
immunopathology.
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Innate immune response
to Virus
Many cell types, but in particular
cells of the innate immune system, express germline‐encoded pattern recognition
receptors (PRRs) that detect invariant molecular structures (pathogen‐associated
molecular patterns, PAMPs) shared by all pathogens of a given class, e.g. all
RNA viruses. With regard to viral infections, nucleic acid‐ and glycoprotein‐PAMPs
act on distinct classes of PRRs, which include certain Toll‐like receptors
(TLRs 2, 3, 7–9 and perhaps 4), retinoic acid inducible gene‐I, melanoma
differentiation‐associated gene 5, dsRNA‐dependent protein kinase and the DNA receptor DAI. These PRRs differ
in their cellular localization, ligand specificity and downstream signalling
pathways, creating a situation where multiple sensor systems have the
opportunity to be involved in the detection of any viral infection of the host.
Upon sensing the invading viral pathogen through the appropriate PRR(s),
multiple distinct signalling pathways become activated; for viruses key
molecules are transcription factors such as interferon regulatory factor (IRF)
3 and 7 as well as nuclear factor κB (NF‐κB). For a more detailed overview of
PRRs and their signalling pathways, we refer the reader to the accompanying
review from the group of S. R. Paludan. Activation of these pathways leads to a
marked reprogramming of the gene expression profile of the cell sensing the
infection and the activation of a wide variety of genes playing a key role in
the innate host defence against viral infection. Thus, the downstream effects
of PRRs signalling include the secretion of proinflammatory cytokines and
chemokines co‐ordinating innate and adaptive immunity. Some of the most
critical mediators in the innate host response to viral infection are the type
I interferons (e.g. IFN‐α and IFN‐β). Type I IFNs in turn induce the expression
of hundreds of IFN‐stimulated genes that may have direct antiviral activity
and/or modulate innate and adaptive immunity by activating immature DCs,
enhancing NK‐cell function and promoting
survival and effector functions of T and B cells.
Role of cytokines
and chemokines
As mentioned above, multiple cytokines
and chemokines are released during viral infection as a consequence of PRR
signalling in cells such as epithelial cells, macrophages and DCs. The major
inflammatory cytokines of the innate response induced by a viral infection
include TNF‐α, type I IFNs, IL‐1, IL‐6, IL‐12 and IL‐18, where type I IFNs
represent key contributors to the activation of innate and adaptive immunity
during viral infection. Unlike type II IFN (IFN‐γ), which is produced
predominantly by primed T cells and activated NK cells, type I IFNs can
essentially be produced by any nucleated cell in response to viral infection,
and all cells can respond to type I IFNs through the type I IFN receptor
(IFNAR), which binds all type I IFN subtypes. However, not all cell types are equally
important in generating an optimal type I IFN response. Thus, it has recently
been found that production of type I IFN from bone marrow‐derived cell types –
as opposed to parenchymal cells – was essential for the early control of virus
replication in several different models of systemic viral infection, strongly
indicating that cells of bone marrow origin are more critical than other cell
populations (regarding this point, see further below). As briefly mentioned,
type I IFNs are induced by the transcription factors IRF3 and IRF7.
While IFN‐β production may be induced
by IRF3 homodimers alone, the production of IFN‐α via both cytosolic and
transmembrane PRR pathways requires the expression of IRF7, either as homodimers
or as heterodimers with IRF3. For this reason, IRF7 has been called the master
regulator of the type I IFN response. IFN‐α/β works in an auto and paracrine
fashion, leading to amplification of the original signal, which in turn induces
a heightened antiviral state. Thus, initially IRF3 and 7 induce small amounts
of IFN‐β/‐α (and other cytokines and chemokines), resulting in type I IFN
signalling via the IFNAR. This induces a marked up‐regulation of IRF7, leading
to full expression of the available type I IFN genes. The end result is secretion
of high levels of cytokines and chemokines, which recruit cells of the innate
immune system including monocytes and NK cells to local virus‐infected tissues,
stimulate NK‐cell activation, induce an antiviral state in neighbouring cells,
amplify DC activation and differentiation and in turn facilitate the induction
of the adaptive immune response.
Interestingly, it was recently shown
that local production of IFN‐β in the central nervous system suppresses
experimental autoimmune encephalomyelitis by inhibiting the expression of
certain chemokines and modulating antigen processing and presentation in
microglia and macrophages. This might be an endogenous protective mechanism
that is elicited upon inflammation of the brain only, an organ that cannot tolerate
inflammation well compared with other organs. Another explanation might be that
IFN‐β initially works in a proinflammatory manner, amplifying the early host
response, and then later plays an anti‐inflammatory role to prevent an
overreaction by the adaptive immune system.
Dcs
DCs provide an important interface
between innate and adaptive immunity. There are two major DC subsets, which
fulfil different, non‐redundant tasks in the formation of the antiviral host
response.
One major DC subset that is particularly
important during viral infection is plasmacytoid DCs (pDCs). These cells
circulate through blood and lymphoid tissues, and compose a specialized subset
of DCs characterized by their ability to produce large amounts of type I IFNs.
Thus, in response to many viruses, pDCs may produce 10‐ to 100‐fold more type I
IFN on a per cell basis compared with other cell types, including other types
of DCs and macrophages. Accordingly, pDCs have been shown to release the first
wave of type I IFNs and may therefore support subsequent steps of antiviral
immunity including NK‐cell activation and T‐cell differentiation in the context
of many viral infections. Moreover, experimental evidence suggests that pDCs
may be recruited to inflammatory sites and draining LNs, and in this manner
become a potent local source of type I IFNs. However, other cell types such as
other types of DCs and macrophages may also significantly contribute to type I
IFN production during viral infection despite their lower per‐cell production
capacity for type I IFNs.
In contrast to their central role in
type I IFN secretion, most studies indicate that pDC are rather inefficient in
presenting antigen to naïve T cells, even though they, to a certain degree, may
be able to activate naïve T cells and induce these to transform into effector
cells. Thus, initial priming of T cells responses in many viral infections
relies predominantly on other types of DCs. Indeed, it was recently reported
that pDCs, activated through TLRs, can induce regulatory T cells, which in turn
may inhibit the expansion of Ag‐primed T cells and thus prevent overstimulation
of the adaptive immune system. However, in the context of viral infection, pDCs
have also recently been found to improve antigen presentation by restoring the
activity and communication of virally perturbed LN–DC networks.
Monocyte/macrophages
Monocyte/macrophages may play a role
in relation to the control of viral infection in two different ways. First,
resident macrophages may constitute an important first line of defence,
together with proinflammatory cytokines and chemokines. Second, as a result of
the induced local inflammatory response additional macrophages are recruited as
a result of transformation of blood‐borne monocytes, which are attracted to the
inflammatory site particularly through their expression of CCR2; these
inflammatory macrophages may be important during the induced innate phase as
well as during the adaptive phase of the host response.
Resident macrophages are ubiquitous
cells strategically placed to act as a first line of defence by their position
near normal portals of viral entry, in LNs and in close contact with
circulating blood. A number of viral models have provided convincing evidence
that macrophages play a key role in many cases of genetically determined innate
resistance to viral infection. One mechanism of how this may work is that macrophages
may be resistant or at least less permissive than other cell types to viral
replication (intrinsic antiviral activity).
Interestingly, some observations
indicate that the initial level of resistance may be regulated by low‐grade
‘spontaneous’ production of type I IFNs. Additionally, macrophages are
themselves potent producers of a range of cytokines including type I IFNs and
the release of soluble mediators may in fact be the most important function
during the early response to viral infection.
Finally, resident macrophages line the
sinuses of the SLO, where they capture small microorganisms and particulate
antigen. These sinuses are also transit zones for pathogen‐loaded DCs, and this
anatomical co‐localization provides the physical basis for the optimal
funnelling of a wide range of antigens into the zones of antigen presentation
within the SLO.
The role of inflammatory macrophages
in the host response to viral infection is less well explored; however, there
are several instances in the literature where prevention of this second wave of
macrophage involvement has been found to markedly affect the outcome of viral
infection. Inflammatory macrophages may also play a key role in the induced
innate response. Thus, during cytomegalovirus infection of the murine liver,
resident macrophages respond to type I IFN by up‐regulation of CCL2, which in
turn recruits CCR2‐expressing inflammatory macrophages; the latter secrete high
amounts of CCL3, which attracts CCR5‐expressing NK cells, a key population in controlling
early viral replication in this infection model.
NK cells
NK cells are another innate effector
cell type that influences the shape of both the innate and the adaptive immune
response during viral infection. NK cells constitutively express transcripts
for certain inflammatory cytokines, e.g. IFN‐γ, and they contain preformed
intracellular granules storing cytolytic mediators such as perforin and
granzymes. The effector functions of activated NK cells therefore include lysis
of virus‐infected cells and the secretion of proinflammatory cytokines (e.g.
IFN‐γ, TNF‐α and GM‐CSF) and chemokines (e.g. CCL4 and CCL5). Through their
soluble mediators, NK cells may themselves augment the local innate
inflammatory response. For example, in the case of murine cytomegalovirus
infection, it has been found that NK‐cell production of IFN‐γ may be essential
to the local secretion of CXCL10 in the liver. As mentioned above, the NK cells
themselves are attracted to the virus‐infected liver through CCL3 produced by
recently recruited inflammatory macrophages.
NK cells are primarily activated by
type I IFNs or proinflammatory cytokines such as IL‐12, IL‐15 and IL‐18, where
DCs are the main source of these cytokines. Notably, different cytokines induce
different aspects of DC‐induced NK‐cell activation and steer the innate immune
response to distinct NK‐cell effector functions. Thus, IL‐12 primarily induces
IFN‐γ secretion by NK cells, while type I IFNs enhance NK cell‐mediated
cytotoxicity, and IL‐15 has the capacity to trigger NK‐cell proliferation and
survival. Interestingly, different DC subsets are known to differ in their
capacity to produce these cytokines. Thus, based on their superior ability to
produce type I IFNs, pDCs mainly enhance NK‐cell cytotoxicity, whereas
conventional (myeloid) DCs mainly stimulate IFN‐γ production and proliferation
by NK cells. Finally, some of these cytokines may trigger the whole spectrum of
NK‐cell activities, provided they are present in high enough concentrations. In
turn, IFN‐γ and TNF‐α produced by NK cells can also affect the maturation and
effector function of neighbouring DCs (up‐regulation of co‐stimulatory molecules
and secretion of cytokines) as well as other leucocytes, including macrophages,
granulocytes and other lymphocytes, which are recruited as a consequence of
viral infection.
NK cells may also be activated through
direct recognition of virus‐infected host cells. This is due to their
expression of a sophisticated repertoire of receptors including NKG2D, which
recognize an array of cellular stress‐induced molecules. Through these
receptors, NK cells are able to distinguish between uninfected, normal cells
and stressed, infected cells. According to the missing self‐hypothesis, NK
cells may also be activated by the loss of MHC expression on some infected
cells. A set of inhibitory receptors normally recognize MHC class I and block
target cell killing, but if the signal from these receptors is too weak,
degranulation and cell killing can be induced. In this manner, NK cells
complement the CD8+ T cells, and viruses trying to avoid CD8+
T cell‐mediated killing through down‐regulation of MHC class I may still be
targeted by the host response. In addition, NK cells express activating
immunoglobulin natural cytotoxicity receptors including CD16, which mediate
antibody‐dependent cellular cytotoxicity, eliminating virus‐infected cells
coated with specific IgG. Direct contact with the infected cells is not,
however, absolutely required for the NK cells to participate in the antiviral
host response, because they can be activated simply by exposure to IFNs and
other cytokines in their environment. Finally, NK cells have also been shown to
express TLR3 and 9, but it is not known whether NK‐cell activation through ligation
of these receptors rather than TLR‐mediated DC activation is important for
viral control.
The immune response to viral infection comprises innate and adaptive defenses. The innate response, which we have discussed previously, functions continuously in a normal host without exposure to any virus. Most viral infections are controlled by the innate immune system. However, if viral replication outpaces innate defenses, the adaptive response must be mobilized.
The adaptive defense consists of antibodies and lymphocytes, often called the humoral response and the cell mediated response. The term ‘adaptive’ refers to the differentiation of self from non-self, and the tailoring of the response to the particular foreign invader. The ability to shape the response in a virus-specific manner depends upon communication between the innate and adaptive systems. This communication is carried out by cytokines that bind to cells, and by cell-cell interactions between dendritic cells and lymphocytes in lymph nodes. This interaction is so crucial that the adaptive response cannot occur without an innate immune system.
The cells of the adaptive immune system are lymphocytes – B cells and T cells. B cells, which are derived from the bone marrow, become the cells that produce antibodies. T cells, which mature in the thymus, differentiate into cells that either participate in lymphocyte maturation, or kill virus-infected cells.
Both humoral and cell mediated responses are essential for antiviral defense. The contribution of each varies, depending on the virus and the host. Antibodies generally bind to virus particles in the blood and at mucosal surfaces, thereby blocking the spread of infection. In contrast, T cells recognize and kill infected cells.
A key feature of the adaptive immune system is memory. Repeat infections by the same virus are met immediately with a strong and specific response that usually effectively stops the infection with less reliance on the innate system. When we say we are immune to infection with a virus, we are talking about immune memory. Vaccines protect us against infection because of immune memory. The first adaptive response against a virus – called the primary response – often takes days to mature. In contrast, a memory response develops within hours of infection. Memory is maintained by a subset of B and T lymphocytes called memory cells which survive for years in the body. Memory cells remain ready to respond rapidly and efficiently to a subsequent encounter with a pathogen. This so-called secondary response is often stronger than the primary response to infection. Consequently, childhood infections protect adults, and immunity conferred by vaccination can last for years.
The nature of the adaptive immune response can clearly determine whether a virus infection is cleared or causes damage to the host. However, an uncontrolled or inappropriate adaptive response can also be damaging. A complete understanding of how viruses cause cause disease requires an appreciation of the adaptive immune response, a subject we’ll take on over the coming weeks.
Conclusions
The effective interplay between the
innate and the adaptive immune response represents a key to survival and is
essentially controlled through the release of cytokines and chemokines from
different cell types initially activated following recognition of viral‐PAMPs.
For a depiction of key events in the cellular interplay underlying the
antiviral host response to a primary viral infection. The first local response
to follow virus attachment and penetration of the epithelial barriers comprises
part of the innate immune response, whose purpose is to activate local cell
types (e.g. resident macrophages) as well as to recruit and activate DCs and
additional antiviral effector cells of the innate defence system to sites of
virus replication. As a consequence, local inflammation is induced through the
production of inflammatory cytokines and chemokines. In this manner, the viral
load is kept low until a more sophisticated adaptive immune response is mounted
and effector T cells can be recruited. The second phase of the local host
response starts when the first antigen‐specific effector T cells enter the
infection site, recognize viral antigen and start releasing their effector
cytokines and chemokines including IFN‐γ and TNF‐α. The latter may act in a
paracrine fashion to induce neighbouring cells including both resident and
recently recruited cells to produce additional cytokines and chemokines. The
recruited T‐cells may also directly and/or indirectly augment the expression of
important vascular adhesion molecules essential to the extravasation of
relevant leucocyte subsets. Together, these events lead to amplification of the
local inflammatory response, and recruitment of more effector cells.
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