Segmented viruses usmle

However, the question remains as to why certain viruses can trigger such excessive responses and to what extent this is related to the genetic or immunological makeup of the host. EBV-driven B cell lymphoproliferative disorders have been extensively studied and arise from latently infected B cells. Of all the different manifestations, which can affect different lymphoid organs and peripheral tissues, BM involvement has been described during infectious mononucleosis and chronic active EBV disease.

Reported BM involvement included pancytopenia, as mentioned before, and detection of proliferating transformed cells Patients with HCV infection develop a number of hematologic disorders, with benign and malignant B cell proliferations being the most common HCV can infect, but not replicate, in B cells, and B cell proliferation in HCV-infected patients seems to result from chronic antigenic stimulation All in all, BM involvement associated with lymphoproliferative disorders and malignancies seem to arise through, yet uncharacterized, indirect mechanisms and not by direct transformation of HSPCs.

In general, most reports regarding the effect of viral infections on BM output refer to pathologic conditions where hematopoiesis is seriously perturbed. It is likely that many acute viral infections induce transient alterations on the hematopoietic process, through the action of mediators such as type I IFNs, TNF, and lymphotoxin LT , as has been described in mice models of lymphocytic choriomeningitis virus LCMV 36 and Influenza infections These effects are most likely overlooked in many human acute viral infections because of their subclinical nature.

Although the particular pathogenic mechanisms underlying all these BM manifestations are not fully understood, two observations seem to stand out from the data. First, many different viruses give rise to the same pathological outcome, which suggests that common underlying mechanisms either of virological or immunological origin might be responsible, and indeed, the immune response plays a major role in the pathogenesis of aplastic anemia and pancytopenia.

Second, the fact that a certain virus can lead to different pathological manifestations in different individuals points to a genetic basis for aberrant immune activation in BM failure, as suggested before 19 , In general, mechanistic studies in animal models are scarce. Dissection of common and pathogen-specific mechanisms could greatly improve therapy and management of affected patients. As a general conclusion, many types of viruses can affect hematopoiesis and, in this section, we have described examples of acute Parvovirus B19, dengue and chronic CMV, HIV , systemic HIV , and localized Influenza infections, which directly or indirectly, transiently or more permanently, affect the hematopoietic process.

In the following sections, we will elaborate on well characterized and also proposed mechanisms behind these processes. Both viruses and immune responses directed toward them have an impact on hematopoiesis. In an elegant review, King and Goodell previously categorized four different mechanisms by which infections in general can influence HSC biology 4. The first two mechanisms act via direct effects on HSCs: 1 direct infection or 2 direct recognition of a pathogen.

The other two mechanisms are indirect: 3 either via pro-inflammatory cytokines released by other cells or 4 through changes in the BM microenvironment. These four scenarios are not mutually exclusive and can even enhance or attenuate each other.

Graphical representation of four different mechanisms by which viral infections can influence the function of HSPCs. The other two mechanisms are indirectly: 3 via inflammatory mediators or 4 through changes in the BM microenvironment. During a viral infection, more than one of these mechanisms contribute to alterations in hematopoiesis, as they are also likely to influence each other, as indicated by the gray arrows.

Better understanding of the complex interactions between these different mechanisms will be important to adequately treat or prevent anemia and BM failure in patients with viral infections. The illustrations used to generate this figure are gratefully obtained from the Powerpoint Image Bank of Servier Medical Art.

For some of these viruses, it has been documented that they can suppress hematopoiesis after direct infection of HSPCs. For example, Simmons et al. Parvovirus B19, the only known human pathogenic parvovirus, has a selective tropism for the erythroid lineage in the BM, where productive infection induces a block in erythropoiesis that can be manifested as a transient or persistent erythroid aplasia Moreover, the consequence of direct viral infection of HSPCs, such as changes in the expression of intracellular factors e.

Prost et al. Overall, direct viral infection in HSPCs has been shown to reduce the hematopoietic output. However, the exact underlying mechanisms after direct virus infections in HSPCs have not been fully elucidated. It has been proposed that direct infection of HSCs does not commonly occur, as they usually reside in protected BM niches 4. Because of this protected microenvironment, quiescent HSCs are thought to be resistant against bacterial infections In fact, all the evidence described in the preceding paragraphs does not distinguish between infection of HSCs or downstream progenitors.

It remains to be determined whether there are any differences in virus susceptibility between these cell types. It is likely that quiescent HSCs are less likely to become infected with a virus compared to their non-quiescent counterparts, and evidence supporting this notion is described in the following section. Pathogen recognition receptors are receptors that detect pathogen-associated molecular patterns PAMPs within the body 48 , It was shown both in vitro and in vivo that direct TLR ligation triggered cell cycle entry in quiescent HSCs, bringing them into a proliferative state 14 , 56 , This indicates an active role for HSCs in immune sensing, and the modulation of early hematopoiesis during infection.

De Luca et al. These different observations could be explained by different sources of cells that were used, as De Luca et al. Although side-by-side validation is lacking, differential TLR expression in fetal vs. Finally, exposure of murine HSPCs to TLR ligands has also been shown to modulate their chemokine receptor expression 6 suggesting that TLR triggering may even regulate their migratory and homing capacities.

In line with this, a comparison of TLR expression patterns between BM resident and mobilized HSPC could reveal interesting differences as to their response to viral infection in terms of lineage commitment and adaptation to demand. It might be that mobilized HSPCs in tissues have an increased surveillance capacity than those in the BM, but this remains to be demonstrated.

Correspondingly, it was demonstrated that the potential of myeloid progenitors to produce DCs was reduced upon TLR9 ligation These findings indicate that TLR9 triggering differentially affects the generation of myeloid vs. Furthermore, in the setting of acute leukemia, Dorantes-Acosta et al. Their findings suggested that B cell development is only marginally influenced by infectious agents, whereas they observed an increased production of myeloid and NK cell types in response to infections and disease-associated cell damage.

Besides affecting lineage commitment, viral sensing might also directly affect HSPC survival. It has, in fact, been shown that RLRs can trigger a dual response in virus-infected cells, which are independent and both contribute to viral control 64 , It is to be expected, given the relevance of maintaining the HSC pool for life, that quiescent HSC are more prone to inducing type I IFN production, which is followed by activation of numerous antiviral mechanisms, instead of inducing the RIPA pathway that kills the cells.

There is potentially less biological cost in inducing RIPA in multipotent progenitors to limit viral replication, because these cells can be replaced by long-term HSCs later on. These results suggest that, compared to downstream progenitors, HSPCs might actually be more prone to activating the IFN antiviral response, although differences between quiescent HSC and multipotent progenitors remain to be shown.

In fact, HSPCs are poorly permissive to both retroviral- and lentiviral-based gene transfer. Lentivirus has the advantage that they do not require cycling cells to integrate their genome and could potentially be more suitable for transformation of quiescent HSCs. Nevertheless, genetic manipulation of HSPCs still requires the use of multiple hits of high vector doses and prolonged ex vivo culture, suggesting that permissiveness is not only dependent on cell-cycle but also on the activation of multiple innate immune sensors and restriction factors that limit viral infection Altogether, it is clear that HSPCs can respond to viral infections through direct recognition of several viral PAMPs, and that the activation of different PRRs can result in different biological outcomes, ranging from changes in chemokine receptor expression and lineage-specification to induction of apoptosis.

In response to PRR ligation by viruses, immune and non-immune cells produce a number of cytokines and chemokines. Different viruses induce slightly different patterns that depend on the interaction of the particular viral PAMP with the specific PRR and the cell type involved 70 , According to Pietras et al.

This proliferative burst fails to exhaust the HSC pool, which rapidly returns to quiescence in response to chronic type I IFN exposure, achieved by repeated polyI:C administration, because of the presence of intrinsic regulatory mechanisms. Type I IFN-exposed HSCs with re-established quiescence are not fully functional but are also largely protected from the killing effects of IFNs unless forced back into the cell cycle due to culture, transplantation, or myeloablative treatment, at which point they activate a pdependent proapoptotic gene program These ideas are further supported by independent findings showing that, when genes that normally suppress IFN signaling are disrupted, mice have increased levels of IFN signaling, and their HSC populations are depleted over time 73 , 76 , Repeated activation of HSCs out of their dormant state provoked their attrition, and this was exacerbated in mice with a defect in DNA repair, suggesting that inefficient repair of replicative DNA damage may result in HSC depletion Again, chronic exposure to polyI:C triggered exhaustion of these stem-cell-like megakaryocyte progenitors and a delayed repletion of platelet counts Collectively, these findings suggest that BM aplasia associated with chronic exposure to type I IFN could arise from a depletion or loss of function of progenitors, together with enforced quiescence of HSCs, which become less functional.

Moreover, if subsequent inflammation or infections force these quiescent HSC chronically exposed to type I IFNs back into cell cycle or if control mechanisms such as those regulating IFN signaling or DNA damage repair are deficient in certain susceptible individuals, this might lead to rapid depletion of the HSC quiescent pool and ensuing BM failure.

This might link the temporal expression of the two types of IFN to the changing needs of the immune response as it progresses from initial innate control to adaptive mechanisms. As mentioned before, PRR stimulation by viruses can also lead to the production of pro-inflammatory cytokines and chemokines, which can in turn affect the proliferation and differentiation of HSCs.

Overall, these results indicate that cytokines can instruct the differentiation and proliferation of HSCs, with BM output being a complex integration of signals from the microenvironment. As with prolonged type I IFN exposure, overproduction of inflammatory cytokines is often associated with hematopoietic failure such as chronic inflammatory diseases and hematopoietic malignancies 33 , but the individual contribution of each player, and their potential synergies and antagonisms, remains to be determined.

Finally, apart from inflammatory cytokines, costimulatory molecules may also play a significant role in altering hematopoiesis during viral infection 5.

This is of interest for the BM, as we previously showed that CDtriggering on HSPCs may serve as a negative feedback mechanism that can regulate hematopoiesis during inflammatory conditions This provides another layer of complexity by which immune activation can modulate the BM output upon viral infection. As described for sterile inflammation and bacterial infections, viral infections may also affect hematopoieisis indirectly via the BM microenvironment.

Apart from hematopoietic cells, the BM also contains non-hematopoietic components, such as osteoblasts, mesenchymal stromal cells MSCs , adipocytes, perivascular cells, endothelial cells, and non-myelinating Schwann cells. It has long been recognized that non-hematopoietic stromal cells in the BM are capable of supporting long-term hematopoiesis in vivo , and that the integrity of several populations of cells is crucial for the long-term maintenance of the quiescent HSC pool 92 , Although the mechanisms have not been clearly dissected, LCMV can infect both stromal cells and megakaryocytic and myelocytic precursors It is likely that the aplasia is a result of apoptosis of the hematopoietic progenitors, which might be modulated by type I IFN signaling, as described above.

However, the effects of viral infection on the stromal cells have not been dissected. It would be very interesting to address whether these cells die from apoptosis or respond by secreting cytokines that can affect hematopoiesis.

If different populations of stromal cells are depleted and the hematopoietic niches are destroyed, the mechanisms by which these niches are reconstituted after viral clearance are still unknown. Importantly, this increase in myelopoiesis was not only seen upon LCMV infection but also upon infection with vesicular stomatitis virus VSV or VV, suggesting that it is a general response to viral infection Mesenchymal stromal cells have also been reported to be affected by HIV, by a mechanism involving Tat and Nef Although no direct link was made, loss of the BM MSC functionality may have consequences on hematopoiesis.

A recent retrospective study has shown that the CMV status of both donor and host are relevant for the overall survival of patients receiving allogeneic stem cell transplantation HSCT As expected, CMV-negative recipients benefit from receiving HSCT from a CMV-negative donor, since the virus transmitted from a seropositive donor into an immunosuppressed seronegative recipient can have devastating effects.

More intriguingly, CMV-positive recipients have an increased overall survival after receiving HSCT from a CMV-positive donor after myeloablative conditioning but not after reduced-intensity conditioning. Interestingly, there were differences in the causes of death between patients with CMV-seropositive or CMV-seronegative donors.

Patients who received grafts from CMV-seronegative donors were more likely to die from viral infection given as the only cause of death or where a viral pathogen was included as a part of a mixed infection with different organisms. This effect was abrogated by T-cell depletion 97 , which suggests that memory T cells from the donor can help control viral infections in situations of more aggressive conditioning.

Since recipient MSCs are not depleted during either of the conditioning regimes 98 , and they can harbor CMV, it would be interesting to study the interaction between donor CMV-specific memory T cells and host CMV-infected stroma, and how this interaction is modulated by the conditioning treatment.

Althof et al. While granulocyte and macrophage progenitors showed a relatively normal proliferative capacity, there was a marked decrease in colony-forming capacity in both erythroid and lymphoid progenitors, indicating a differential impact on the various HSPC subsets Production of type I IFNs was shown to contribute to the development of lymphopenia upon CVB infection 99 , which could also further contribute to the hematopoietic defects of the other hematopoietic lineages.

Scumpia et al. They suggest that reduction in BM cellularity alone is sufficient to induce HSPC expansion, possibly mediated by supporting stromal cells that can provide the necessary signals for HSPC expansion within the BM space left void following infection or chemotherapeutic BM ablation Similarly, it has been suggested that granulopoiesis can be driven by the number of neutrophils present in the BM.

On the other hand, at high neutrophil numbers, the production of IL in DCs and macrophages is inhibited by the phagocytosis of apoptotic neutrophils, resulting in a negative feedback loop Large numbers of neutrophils are predominantly important in fungal and bacterial infections, and whether similar interactions are at play in viral infections is currently unknown.

However, it is an interesting concept that the sheer presence or absence of particular cell types in the BM can also contribute to the virally induced hematopoietic stress response. Overall, the link between the BM microenvironment and hematopoiesis is not easy to define. Multiple pathways can play a role in the regulation of hematopoiesis via the BM microenvironment, and these pathways may further complement each other.

Yet, understanding the underlying cellular and molecular mechanisms by which the BM responds to viral infections may help us to counteract the ensuing pathogenic consequences, which were discussed at the beginning of this review. Viral infections can cause direct and indirect damage to HSPCs and the surrounding tissue. Direct pathogenic effects depend on viral tropism and viral cycle, and there are a few examples of direct infection of HSPCs that lead to altered BM output, e.

Acute viral infections usually cause transient aplasia, partly related to the effect of type I IFNs, and to direct viral infection, in which both HSPCs and stromal cells are depleted. However, very little is known about how MSCs and other stromal cells recover from acute damage and by which mechanisms the different BM niches are reconstituted after resolution of infection.

Insights into these processes could help understand BM repair in other situations, such as after radiation or chemotherapy. This information has direct translatable potential into the clinic, as enhanced niche reconstitution could be highly beneficial after HSC transplantation. Finally, a link between direct viral infection of HSPCs and transformation has not been found.

Instead, some hyperproliferative syndromes arise after infection of mature B cells, and BM involvement appears as a secondary condition. However, BM pathologies are rare events and often associated to alterations in gene regulation of cytokines, effector, and MHC molecules, which suggest a genetic basis for aberrant T cell activation in BM failure [reviewed in Ref.

Furthermore, one final interesting aspect that deserves exploring is the concept of the BM as a site of immune privilege. Although this concept was tested under conditions of allogeneic HSC transplant, there are no examples of control of antiviral responses by BM Tregs. It would be very interesting to dissect how Tregs shape the interactions between viruses, HSPCs, and stroma, and how this affects viral clearance, skewing of hematopoiesis, and niche regeneration.

Overall, hematopoiesis is a very flexible process that quickly adapts to the needs of the host, providing an adjusted cellular output to fight off a certain pathogen. While considerable insight has been gathered regarding the regulation of BM output by general inflammatory processes and bacterial infections, less is known about the specific regulation of hematopoiesis by viral infections.

Some of the previously described mechanisms also apply to this situation. Yet, our understanding of the full breadth by which viral infections affect hematopoiesis remains limited. It is thus important to further unravel the responsible cellular and molecular players in this process and their complex interplay in order to adequately treat or prevent anemia and BM failure in patients with viral infections.

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. National Center for Biotechnology Information , U. Front Immunol. Published online Sep Martje N. Martijn A.

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